US20220125773A1 - Aqueous formulations of water insoluble cox-2 inhibitors - Google Patents
Aqueous formulations of water insoluble cox-2 inhibitors Download PDFInfo
- Publication number
- US20220125773A1 US20220125773A1 US17/512,268 US202117512268A US2022125773A1 US 20220125773 A1 US20220125773 A1 US 20220125773A1 US 202117512268 A US202117512268 A US 202117512268A US 2022125773 A1 US2022125773 A1 US 2022125773A1
- Authority
- US
- United States
- Prior art keywords
- pharmaceutical composition
- cyclodextrin
- inhibitor
- cox
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 303
- 229940111134 coxibs Drugs 0.000 title claims abstract description 154
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 title claims abstract description 154
- 239000013011 aqueous formulation Substances 0.000 title claims abstract description 57
- 239000000203 mixture Substances 0.000 claims abstract description 142
- 238000000034 method Methods 0.000 claims abstract description 71
- 239000002904 solvent Substances 0.000 claims abstract description 62
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 152
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical group C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 107
- 229960000371 rofecoxib Drugs 0.000 claims description 106
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 101
- 229920000858 Cyclodextrin Polymers 0.000 claims description 91
- 229960004853 betadex Drugs 0.000 claims description 87
- 229940100688 oral solution Drugs 0.000 claims description 87
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 80
- 208000002193 Pain Diseases 0.000 claims description 43
- 239000000243 solution Substances 0.000 claims description 39
- 239000003963 antioxidant agent Substances 0.000 claims description 37
- 230000036407 pain Effects 0.000 claims description 37
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical group O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 37
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 36
- 238000009472 formulation Methods 0.000 claims description 36
- 230000003078 antioxidant effect Effects 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 30
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 28
- 239000006172 buffering agent Substances 0.000 claims description 27
- 239000001116 FEMA 4028 Substances 0.000 claims description 24
- 238000001990 intravenous administration Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 150000002148 esters Chemical class 0.000 claims description 21
- 238000002648 combination therapy Methods 0.000 claims description 18
- 229960000590 celecoxib Drugs 0.000 claims description 17
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 17
- 229960004945 etoricoxib Drugs 0.000 claims description 17
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 claims description 17
- 229940124597 therapeutic agent Drugs 0.000 claims description 17
- 239000013078 crystal Substances 0.000 claims description 16
- 239000006184 cosolvent Substances 0.000 claims description 15
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 14
- 206010037660 Pyrexia Diseases 0.000 claims description 13
- ODLHGICHYURWBS-FOSILIAISA-N molport-023-220-444 Chemical compound CC(O)COC[C@@H]([C@@H]([C@H]([C@@H]1O)O)O[C@@H]2O[C@H]([C@H](O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O3)[C@@H](O)[C@@H]2O)COCC(O)C)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O)[C@H]3O[C@H]1COCC(C)O ODLHGICHYURWBS-FOSILIAISA-N 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 8
- 239000007951 isotonicity adjuster Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 110
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 102
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 53
- 229920001223 polyethylene glycol Polymers 0.000 description 52
- 229920001983 poloxamer Polymers 0.000 description 34
- 235000006708 antioxidants Nutrition 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 239000003981 vehicle Substances 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 201000010099 disease Diseases 0.000 description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 238000012216 screening Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 10
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 10
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 9
- 238000001356 surgical procedure Methods 0.000 description 9
- -1 cyclic oligosaccharide Chemical class 0.000 description 7
- 239000007935 oral tablet Substances 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 208000004550 Postoperative Pain Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 230000002526 effect on cardiovascular system Effects 0.000 description 5
- 238000009533 lab test Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 238000011477 surgical intervention Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RAECDKKKKNJXTF-UHFFFAOYSA-N 3-(4-methylsulfinylphenyl)-4-phenyl-2h-furan-5-one Chemical compound C1=CC(S(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RAECDKKKKNJXTF-UHFFFAOYSA-N 0.000 description 4
- LJZJWBAPABMSII-UHFFFAOYSA-N 3-(4-methylsulfonylphenyl)-4-phenylfuran-2,5-dione Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1=O LJZJWBAPABMSII-UHFFFAOYSA-N 0.000 description 4
- 235000005979 Citrus limon Nutrition 0.000 description 4
- 244000131522 Citrus pyriformis Species 0.000 description 4
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000020971 citrus fruits Nutrition 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- 238000013498 data listing Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 208000004296 neuralgia Diseases 0.000 description 4
- 229940096978 oral tablet Drugs 0.000 description 4
- 229960005489 paracetamol Drugs 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920001993 poloxamer 188 Polymers 0.000 description 4
- 229940044519 poloxamer 188 Drugs 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 235000012424 soybean oil Nutrition 0.000 description 4
- 239000003549 soybean oil Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 238000009528 vital sign measurement Methods 0.000 description 4
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 3
- 244000144725 Amygdalus communis Species 0.000 description 3
- 241000167854 Bourreria succulenta Species 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 3
- 240000006909 Tilia x europaea Species 0.000 description 3
- 235000011941 Tilia x europaea Nutrition 0.000 description 3
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 3
- 208000005298 acute pain Diseases 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 3
- 235000019693 cherries Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 229960002737 fructose Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 239000004571 lime Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 3
- WTEVQBCEXWBHNA-YFHOEESVSA-N neral Chemical compound CC(C)=CCC\C(C)=C/C=O WTEVQBCEXWBHNA-YFHOEESVSA-N 0.000 description 3
- 229960002715 nicotine Drugs 0.000 description 3
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 3
- 239000000820 nonprescription drug Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000008174 sterile solution Substances 0.000 description 3
- 239000007916 tablet composition Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 206010049589 Afterbirth pain Diseases 0.000 description 2
- 235000011437 Amygdalus communis Nutrition 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- WTEVQBCEXWBHNA-UHFFFAOYSA-N Citral Natural products CC(C)=CCCC(C)=CC=O WTEVQBCEXWBHNA-UHFFFAOYSA-N 0.000 description 2
- 208000006561 Cluster Headache Diseases 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 208000008930 Low Back Pain Diseases 0.000 description 2
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 2
- 235000009421 Myristica fragrans Nutrition 0.000 description 2
- 208000001294 Nociceptive Pain Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000004983 Phantom Limb Diseases 0.000 description 2
- 206010056238 Phantom pain Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 206010061363 Skeletal injury Diseases 0.000 description 2
- 239000004376 Sucralose Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 235000009754 Vitis X bourquina Nutrition 0.000 description 2
- 235000012333 Vitis X labruscana Nutrition 0.000 description 2
- 240000006365 Vitis vinifera Species 0.000 description 2
- 235000014787 Vitis vinifera Nutrition 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 235000020224 almond Nutrition 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 229960001305 cysteine hydrochloride Drugs 0.000 description 2
- 201000003146 cystitis Diseases 0.000 description 2
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical compound CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- SSNZFFBDIMUILS-UHFFFAOYSA-N dodec-2-enal Chemical compound CCCCCCCCCC=CC=O SSNZFFBDIMUILS-UHFFFAOYSA-N 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 235000020650 eye health related herbal supplements Nutrition 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 2
- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 2
- 229960004752 ketorolac Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 2
- 208000021722 neuropathic pain Diseases 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 238000009597 pregnancy test Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000000473 propyl gallate Substances 0.000 description 2
- 235000010388 propyl gallate Nutrition 0.000 description 2
- 229940075579 propyl gallate Drugs 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000934 spermatocidal agent Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 201000009032 substance abuse Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000006068 taste-masking agent Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000002562 urinalysis Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 208000009935 visceral pain Diseases 0.000 description 2
- 239000004034 viscosity adjusting agent Substances 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- UIKROCXWUNQSPJ-VIFPVBQESA-N (-)-cotinine Chemical compound C1CC(=O)N(C)[C@@H]1C1=CC=CN=C1 UIKROCXWUNQSPJ-VIFPVBQESA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- CBOBADCVMLMQRW-UHFFFAOYSA-N 2,6-dimethyloctanal Chemical compound CCC(C)CCCC(C)C=O CBOBADCVMLMQRW-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-UHFFFAOYSA-N 0.000 description 1
- MJKVTPMWOKAVMS-UHFFFAOYSA-N 3-hydroxy-1-benzopyran-2-one Chemical class C1=CC=C2OC(=O)C(O)=CC2=C1 MJKVTPMWOKAVMS-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 244000099147 Ananas comosus Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- 229940022962 COVID-19 vaccine Drugs 0.000 description 1
- 101100298998 Caenorhabditis elegans pbs-3 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 244000037364 Cinnamomum aromaticum Species 0.000 description 1
- 235000014489 Cinnamomum aromaticum Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 235000019499 Citrus oil Nutrition 0.000 description 1
- 241001672694 Citrus reticulata Species 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 241000777300 Congiopodidae Species 0.000 description 1
- UIKROCXWUNQSPJ-UHFFFAOYSA-N Cotinine Natural products C1CC(=O)N(C)C1C1=CC=CN=C1 UIKROCXWUNQSPJ-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000037194 Fever of Unknown Origin Diseases 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 206010018001 Gastrointestinal perforation Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019345 Heat stroke Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241000220225 Malus Species 0.000 description 1
- 235000011430 Malus pumila Nutrition 0.000 description 1
- 235000015103 Malus silvestris Nutrition 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 240000005561 Musa balbisiana Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- 244000270834 Myristica fragrans Species 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010048737 Poor venous access Diseases 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 208000000399 Procedural Pain Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000003893 Prunus dulcis var amara Nutrition 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 240000001987 Pyrus communis Species 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 240000007651 Rubus glaucus Species 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 208000037847 SARS-CoV-2-infection Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000003490 Thiodipropionic acid Substances 0.000 description 1
- 208000003441 Transfusion reaction Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 244000263375 Vanilla tahitensis Species 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000010617 anise oil Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000010692 aromatic oil Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 239000010620 bay oil Substances 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- YNKMHABLMGIIFX-UHFFFAOYSA-N benzaldehyde;methane Chemical compound C.O=CC1=CC=CC=C1 YNKMHABLMGIIFX-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 238000009811 bilateral tubal ligation Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 208000027499 body ache Diseases 0.000 description 1
- 239000008372 bubblegum flavor Substances 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229940119201 cedar leaf oil Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000002192 cholecystectomy Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 239000010630 cinnamon oil Substances 0.000 description 1
- 229940043350 citral Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000010500 citrus oil Substances 0.000 description 1
- 239000010634 clove oil Substances 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940126523 co-drug Drugs 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 229950006073 cotinine Drugs 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 150000004659 dithiocarbamates Chemical class 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 201000005311 drug allergy Diseases 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000000001 effect on platelet aggregation Effects 0.000 description 1
- 238000002565 electrocardiography Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000012953 feeding on blood of other organism Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 239000008369 fruit flavor Substances 0.000 description 1
- 230000008571 general function Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940087068 glyceryl caprylate Drugs 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000009802 hysterectomy Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000001115 mace Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 239000001683 mentha spicata herb oil Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 229940015769 nicotine chewing gum Drugs 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- GYHFUZHODSMOHU-UHFFFAOYSA-N nonanal Chemical compound CCCCCCCCC=O GYHFUZHODSMOHU-UHFFFAOYSA-N 0.000 description 1
- 239000001702 nutmeg Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- NUJGJRNETVAIRJ-UHFFFAOYSA-N octanal Chemical compound CCCCCCCC=O NUJGJRNETVAIRJ-UHFFFAOYSA-N 0.000 description 1
- 229940051776 ofirmev Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000008601 oleoresin Substances 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000007967 peppermint flavor Substances 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001622 pimenta officinalis fruit oil Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- SDUIIRKPTNAXJI-UHFFFAOYSA-M sodium 2-hydroxypropan-2-yl sulfate Chemical compound [Na+].CC(C)(O)OS([O-])(=O)=O SDUIIRKPTNAXJI-UHFFFAOYSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 235000019303 thiodipropionic acid Nutrition 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 239000001789 thuja occidentalis l. leaf oil Substances 0.000 description 1
- 239000010678 thyme oil Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003802 tocotrienol Natural products 0.000 description 1
- 239000011731 tocotrienol Substances 0.000 description 1
- 235000019148 tocotrienols Nutrition 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- Analgesics to control postoperative pain can be administered immediately prior to surgery (preoperatively), during surgery (intraoperatively), after surgery (postoperatively), or following hospital discharge via a prescription.
- Commonly used drug classes include opioids, acetaminophen, nonselective NSAIDs, and local anesthetics.
- opioids include opioids, acetaminophen, nonselective NSAIDs, and local anesthetics.
- acetaminophen nonselective NSAIDs
- local anesthetics local anesthetics.
- intravenously administered analgesics is dominated by two agents: IV ketorolac (TORADOL) and IV acetaminophen (OFIRMEV).
- IV ketorolac is widely used because of its strong efficacy profile, but it carries several important limitations, including a significant risk of serious gastrointestinal (GI) bleeds, an indication that is limited to short-term ( ⁇ 5 days) use in adults only, and a contra-indication for pre-operative use, due to its effect on platelet aggregation.
- IV acetaminophen is recognized as safer than IV ketorolac, but is limited in use due to its modest efficacy at treating pain.
- NSAIDs have pain-relieving, antipyretic and anti-inflammatory properties, are proven to be effective following day surgery and minor surgery, and have an opiate-sparing effect after more major surgery.
- COX-2 inhibitors are a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs) that have been shown to be highly effective in treating conditions such as acute pain, and may be administered to patients with a high risk of operative site bleeding, upper GI bleeding or those with a history of peptic ulcer.
- NSAIDs nonsteroidal anti-inflammatory drugs
- Few, if any, COX-2 selective NSAIDs are available in a formulation that is suitable for use in an intravenous or other parenteral administration, due to the fact that they are insoluble or practically insoluble in water.
- These water insoluble COX-2 inhibitors include rofecoxib, etoricoxib, and celecoxib. Described herein are aqueous formulations of water insoluble COX-2 inhibitors suitable for oral or intravenous or other parenteral administration.
- the subject matter disclosed herein provides a pharmaceutical composition
- a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and c) a solubilizing agent, wherein the solubility of the water insoluble COX-2 inhibitor in the solution is more than 10 ⁇ g/ml.
- the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent.
- said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted prior to administration.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the ⁇ -cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the effective amount of the water insoluble COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the concentration % (w/v) of the water insoluble COX-2 inhibitor in the solution is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration.
- the volume of the solution is selected from the group consisting of about 5 mL, about 10 ml, about 20 ml, about 25 mL, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume.
- the solubility of the water insoluble COX-2 inhibitor in the solution is more than 20 ⁇ g/ml, more than 30 ⁇ g/ml, more than 40 ⁇ g/ml, more than 50 ⁇ g/ml, more than 60 ⁇ g/ml, more than 70 ⁇ g/ml, more than 80 ⁇ g/ml, more than 90 ⁇ g/ml, more than 100 ⁇ g/ml, more than 110 ⁇ g/ml, more than 120 ⁇ g/ml, more than 130 ⁇ g/ml, more than 140 ⁇ g/ml, or more than 150 ⁇ g/ml.
- said composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, said composition is suitable for intravenous administration to a subject.
- the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a lyophilization product of any of the pharmaceutical compositions described herein.
- the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising parenterally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a COX-2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and c) a solubilizing agent.
- the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib.
- the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent. In some embodiments, said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the ⁇ -cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the effective amount of the COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the concentration % (w/v) of the COX-2 inhibitor in an aqueous formulation is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration.
- the volume of an aqueous formulations of the COX-2 inhibitor is selected from the group consisting of about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 10 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume.
- the solubility of the COX-2 inhibitor is enhanced to more than 10 ⁇ g/ml, more than 20 ⁇ g/ml, more than 30 ⁇ g/ml, more than 40 ⁇ g/ml, more than 50 ⁇ g/ml, more than 60 ⁇ g/ml, more than 70 ⁇ g/ml, more than 80 ⁇ g/ml, more than 90 ⁇ g/ml, more than 100 ⁇ g/ml, more than 110 ⁇ g/ml, more than 120 ⁇ g/ml, more than 130 ⁇ g/ml, more than 140 ⁇ g/ml, or more than 150 ⁇ g/ml.
- said composition is administered as part of a combination therapy with at least one other therapeutic agent.
- the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof and a solubilizing agent, wherein the lyophilized pharmaceutical composition is a produced by lyophilizing a pharmaceutical composition comprising an aqueous formulation comprising water, a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and a solubilizing agent.
- the subject matter disclosed herein provides a pharmaceutical composition
- a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent.
- the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the 3-cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the pharmaceutical composition comprises an effective amount of the COX-2 inhibitor in a single dose, wherein the effective amount is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the effective amount is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13
- the pharmaceutical composition has a volume of the oral solution selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume.
- the pharmaceutical composition the oral solution comprises of about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
- the pharmaceutical composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, the pharmaceutical composition is suitable for oral administration to a subject.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC 0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma AUC 0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml.
- the oral solution comprising rofecoxib achieves a plasma AUC 0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma C max from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma C max is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml.
- the oral solution comprising rofecoxib achieves a C max of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
- the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent.
- a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent.
- the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the 3-cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the method comprises an effective amount of the COX-2 inhibitor in a single dose selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the oral solution has a volume selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume.
- the oral solution comprises about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
- the composition is administered as part of a combination therapy with at least one other therapeutic agent.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC 0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma AUC 0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml.
- the oral solution comprising rofecoxib achieves a plasma AUC 0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma C max from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma C max is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml.
- the oral solution comprising rofecoxib achieves a C max of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
- FIG. 1 shows results summary for screening vehicle compositions 169-203.
- FIG. 2 shows results summary for screening vehicle compositions 204-219.
- FIG. 3 shows results summary for screening vehicle compositions 135-168.
- FIG. 4 shows Cmax values for the tablet and oral solution (OS) formulations of rofecoxib.
- FIG. 5 shows AUC for the tablet and oral solution (OS) formulations of rofecoxib.
- “solubilizing agent” refers to, but is not limited to, a cyclodextrin, a polyethylene glycol, a protic solvent, a dipolar aprotic solvent, a lipid, or a surfactant.
- Cyclodextrin refers to a cyclic oligosaccharide. Cyclodextrin includes, but is not limited to, the compounds known as ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin, and derivatives thereof.
- a “water insoluble COX-2 inhibitor” includes any COX-2 inhibitor which is insoluble or practically insoluble in water.
- Water insoluble COX-2 inhibitor includes rofecoxib, etoricoxib, celecoxib, and pharmaceutically acceptable salts, esters, or co-crystals thereof.
- treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
- an effective amount refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome.
- an effective amount is a therapeutically effective amount.
- a therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject.
- the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition.
- One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
- administer refers to the methods used to enable delivery of a pharmaceutical compositions to the targeted location of biological action.
- acceptable with respect to a pharmaceutical composition refers to the composition having no persistent detrimental effect on the general health of a subject being treated.
- antioxidant refers to a pharmaceutical compound that prevents oxygen or oxygen-derived free radicals from interacting with other substances.
- the general function of antioxidants in compositions is to minimize or distort the oxidative processes that occur with some pharmaceutical compounds or excipients upon exposure to oxygen or in the presence of free radicals.
- co-administration means the administration of two agents (e.g. concomitantly or sequentially) in any manner in which the pharmacological effects of both are manifest in the subject at the same time.
- Concomitant administration does not require that both agents be administered in a single pharmaceutical composition, in the same dosage form, or by the same route of administration.
- the effects of both agents need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive.
- the term “subject” refers to a vertebrate animal.
- the subject is a mammal or a mammalian species.
- the subject is a human.
- the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals.
- the term “patient” refers to a human or animal.
- the term “mammal” includes, but is not limited to, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, the mammal is a human.
- pain refers to all types of pain, including, but not limited, to nociceptive pain, neuropathic pain, post-operative pain, lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, migraine, and genitourinary tract-related pain including cystitis.
- the subject matter disclosed herein provides a pharmaceutical composition
- a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and c) a solubilizing agent, wherein the solubility of the water insoluble COX-2 inhibitor in the solution is more than 10 ⁇ g/ml.
- the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent.
- said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted prior to administration.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the ⁇ -cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the effective amount of the water insoluble COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the concentration % (w/v) of the water insoluble COX-2 inhibitor in the solution is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration.
- the volume of the solution is selected from the group consisting of about 5 mL, about 10 ml, about 20 ml, about 25 mL, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume.
- the solubility of the water insoluble COX-2 inhibitor in the solution is more than 20 ⁇ g/ml, more than 30 ⁇ g/ml, more than 40 ⁇ g/ml, more than 50 ⁇ g/ml, more than 60 ⁇ g/ml, more than 70 ⁇ g/ml, more than 80 ⁇ g/ml, more than 90 ⁇ g/ml, more than 100 ⁇ g/ml, more than 110 ⁇ g/ml, more than 120 ⁇ g/ml, more than 130 ⁇ g/ml, more than 140 ⁇ g/ml, or more than 150 ⁇ g/ml.
- said composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, said composition is suitable for intravenous administration to a subject.
- the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a lyophilization product of any of the pharmaceutical compositions described herein.
- the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising parenterally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a COX-2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and c) a solubilizing agent.
- the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib.
- the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent. In some embodiments, said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the ⁇ -cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the effective amount of the COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the concentration % (w/v) of the COX-2 inhibitor in an aqueous formulation is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration.
- the volume of an aqueous formulations of the COX-2 inhibitor is selected from the group consisting of about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 10 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume.
- the solubility of the COX-2 inhibitor is enhanced to more than 10 ⁇ g/ml, more than 20 ⁇ g/ml, more than 30 ⁇ g/ml, more than 40 ⁇ g/ml, more than 50 ⁇ g/ml, more than 60 ⁇ g/ml, more than 70 ⁇ g/ml, more than 80 ⁇ g/ml, more than 90 ⁇ g/ml, more than 100 ⁇ g/ml, more than 110 ⁇ g/ml, more than 120 ⁇ g/ml, more than 130 ⁇ g/ml, more than 140 ⁇ g/ml, or more than 150 ⁇ g/ml.
- said composition is administered as part of a combination therapy with at least one other therapeutic agent.
- the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof and a solubilizing agent, wherein the lyophilized pharmaceutical composition is a produced by lyophilizing a pharmaceutical composition comprising an aqueous formulation comprising water, a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and a solubilizing agent.
- the subject matter disclosed herein provides a pharmaceutical composition
- a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent.
- the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the 3-cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the pharmaceutical composition comprises an effective amount of the COX-2 inhibitor in a single dose, wherein the effective amount is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the effective amount is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13
- the pharmaceutical composition has a volume of the oral solution selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume.
- the pharmaceutical composition the oral solution comprises of about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
- the pharmaceutical composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, the pharmaceutical composition is suitable for oral administration to a subject.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC 0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma AUC 0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml.
- the oral solution comprising rofecoxib achieves a plasma AUC 0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma C max from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma C max is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml.
- the oral solution comprising rofecoxib achieves a C max of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
- the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent.
- a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent.
- the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- the solubilizing agent is a cyclodextrin.
- the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, and any mixtures thereof.
- the ⁇ -cyclodextrin is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
- the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®.
- the 3-cyclodextrin is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
- the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the method comprises an effective amount of the COX-2 inhibitor in a single dose selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the oral solution has a volume selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume.
- the oral solution comprises about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
- the composition is administered as part of a combination therapy with at least one other therapeutic agent.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC 0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma AUC 0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml.
- the oral solution comprising rofecoxib achieves a plasma AUC 0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- the oral solution comprises rofecoxib and achieves a geometric mean plasma C max from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
- the geometric mean plasma C max is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml.
- the oral solution comprising rofecoxib achieves a C max of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
- the solubilizing agent is a cyclodextrin.
- the COX-2 inhibitor is rofecoxib.
- the COX-2 inhibitor is etoricoxib.
- the COX-2 inhibitor is celecoxib.
- the pharmaceutical compositions described herein comprise an aqueous solution including water, a solubilizing agent, and a water insoluble COX-2 inhibitor.
- the solubilizing agent is a cyclodextrin.
- the solubilizing agent comprises a polyethylene glycol. Exemplary embodiments of polyethylene glycol include, but are not limited to, PEG300 and PEG400.
- the solubilizing agent is Soluplus®.
- the solubilizing agent is a protic solvent.
- the solubilizing agent is a dipolar aprotic solvent, for example DMSO or DMF.
- the solubilizing agent is a lipid.
- the solubilizing agent is soybean oil.
- the solubilizing agent is a surfactant, for example Kolliphor®, polysorbate 20 (PS 20), or polysorbate 80 (PS 80).
- the solubilizing agent is a co-solvent helper such as ethanol.
- pharmaceutical compositions may include more than one solubilizing agent.
- the solubilizing agents include a cyclodextrin and a polyethylene glycol.
- the solubilizing agents include a cyclodextrin and Soluplus®.
- the pharmaceutical compositions are suitable for administration to a subject.
- the pharmaceutical compositions are suitable for oral or parenteral administration to a human.
- the pharmaceutical compositions are suitable for intravenous administration to a human.
- the pharmaceutical compositions described herein are in a dose unit that is “ready to use” for injection or other parenteral administration.
- the pharmaceutical compositions described herein are diluted with a sterile solution prior to administration.
- the pharmaceutical compositions described herein are formed by reconstituting a lyophilization product (e.g., a powder) with a sterile solution.
- the cyclodextrin is a cyclic oligosaccharide. In some embodiments, the cyclodextrin is a ⁇ -cyclodextrin or a derivative thereof. In some embodiments, the cyclodextrin is an ⁇ -cyclodextrin or a derivative thereof. In some embodiments, the cyclodextrin is a ⁇ -cyclodextrin or a derivative thereof.
- the ⁇ -cyclodextrin derivative is a hydroxypropyl- ⁇ -cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl- ⁇ -cyclodextrin is Cavasol®. In some embodiments, the ⁇ -cyclodextrin derivative is a sulfobutyl ether- ⁇ -cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether- ⁇ -cyclodextrin is Captisol®.
- the “water insoluble COX-2 inhibitor” is a COX-2 inhibitor which is insoluble or practically insoluble in water.
- the water insoluble COX-2 inhibitor is rofecoxib.
- the water insoluble COX-2 inhibitor is etoricoxib.
- the water insoluble COX-2 inhibitor is celecoxib.
- the water insoluble COX-2 inhibitor has a solubility of less than 10 ⁇ g/ml.
- the total amount of the one or more solubilizing agent in the aqueous solution is about 5% (w/v), 10% (w/v), 15% (w/v), 20% (w/v), 25% (w/v), 30% (w/v), 35% (w/v), 40% (w/v/), 45% (w/v), 50% (w/v), 55% (w/v), 60% (w/v), 70% (w/v), 80% (w/v) or more.
- the total amount of solubilizing agent(s) in the aqueous solution is about 5% (v/v), 10% (v/v), 15% (w/v), 20% (v/v), 25% (v/v), 30% (v/v), 35% (v/v), 40% (v/v/), 45% (v/v), 50% (v/v), 55% (v/v), 60% (v/v), 70% (w/v), 80% (v/v) or more.
- the total amount of the solubilizing agent(s) in the aqueous formulation ranges from 5-10% (w/v), 10-15% (w/v), 15-20% (w/v), 20-25% (w/v), 25-30% (w/v), 30-35% (w/v), 35-40% (w/v), 40-45% (w/v), 45-50% (w/v), 50-55% (w/v), or 55-60% (w/v), or 60-80% (w/v).
- the total amount of solubilizing agent(s) in the aqueous formulation ranges from 5-10% (v/v), 10-15% (v/v), 15-20% (v/v), 20-25% (v/v), 25-30% (v/v), 30-35% (v/v), 35-40% (v/v), 40-45% (v/v), 45-50% (v/v), 50-55% (v/v), 55-60% (v/v), or 60-80% (v/v).
- the subject matter described herein relates to enhanced solubility of water insoluble COX-2 inhibitors.
- the solubility of COX-2 inhibitors is enhanced to more than 10 ⁇ g/ml, more than 20 ⁇ g/ml, more than 30 ⁇ g/ml, more than 40 ⁇ g/ml, more than 50 ⁇ g/ml, more than 60 ⁇ g/ml, more than 70 ⁇ g/ml, more than 80 ⁇ g/ml, more than 90 ⁇ g/ml, more than 100 ⁇ g/ml, more than 110 ⁇ g/ml, more than 120 ⁇ g/ml, more than 130 ⁇ g/ml, more than 140 ⁇ g/ml, or more than 150 ⁇ g/ml.
- the solubility of the water insoluble COX-2 inhibitors is measured at 4 hours. In some embodiments, the solubility of the water insoluble COX-2 inhibitors is measured at 24 hours. In some embodiments, the solubility of the water insoluble COX-2 inhibitors is measured at 48 hours.
- the pharmaceutical compositions described herein include one or more viscosity modifiers.
- the viscosity modifier is benzyl alcohol.
- the pharmaceutical composition described herein also contains at least one antioxidant, which may increase the stability of the COX-2 inhibitor in solution.
- suitable antioxidants include, but are not limited to, citric acid monohydrate, histidine, monothioglycerol, niacinamide, phosphoric acid, potassium metabisulfite, sodium ascorbate, sodium bisulfate acetone, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, tartaric acid, or any derivative or combination thereof.
- antioxidants include, but are not limited to, cysteine hydrochloride monohydrate, thiolyglycolic acid, thiolacetic acid, dithiothreitol, reduced glutathione, thiourea, alpha-thioglycerol, cysteine, acetylcysteine, methionine, mercaptoethane, sulfonic acid, metabisulfite, ascorbic acid ascorbic acid derivatives (e.g., ascorbyl palmitate), sodium citrate, an organic compound having at least one thiol, an alkyl polyhydroxylated compound, a cycloalkyl polyhydroxylated compound, a hydroxypolycarboxylic acid, an alpha-hydroxy polycarboxylic acid (e.g., citric acid), tocotrienol, dimethyl glycine, betaine, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, polyethylene glycol,
- the pharmaceutical composition is free of polyethylene glycol or a derivative thereof. In other embodiments, the pharmaceutical composition is free of sulfites.
- the antioxidant is cysteine hydrochloride monohydrate. In some embodiments, the antioxidant is mannitol.
- the antioxidant is any antioxidant that can be used with the pharmaceutical compositions described herein.
- the antioxidant is in a solution form before it is incorporated into a pharmaceutical composition.
- the antioxidant solution includes ethanol.
- the antioxidant solution may be the same as a solubilizing agent, such as ethanol.
- the antioxidant helps prevent formation of an oxidation product of rofecoxib, including 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione, 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone, and/or dicarboxylate derivative of rofecoxib.
- the antioxidant reduces the formation of 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione, 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone, and/or dicarboxylate derivative of rofecoxib by 5%, 10%, 15%, 20%, 25%, 50%, or 75% or more.
- the amount % (w/w) of the antioxidant in a solid or lyophilized formulation of the water insoluble COX-2 inhibitor prior to reconstitution is about 0.01% (w/w) to about 5.0% (w/w). In some embodiments, the amount % (w/w) of the antioxidant is about 0.01% (w/w), 0.05% (w/w), 0.10% (w/w), 0.15% (w/w), about 0.17% (w/w), about 0.20% (w/w), about 0.30% (w/w), about 0.40% (w/w), about 0.45% (w/w), about 0.50% (w/w), about 0.52% (w/w), about 0.55% (w/w), about 0.60% (w/w), about 0.70% (w/w), about 0.80% (w/w), about 1.0% (w/w), about 1.3% (w/w), about 1.5% (w/w), about 1.7% (w/w), about 2.0% (w/w), about 2.2% (w/w),
- the concentration of the antioxidant in an aqueous formulation of a water insoluble COX-2 inhibitor prior to administration ranges from about 0.01 mg/ml to about 10 mg/ml.
- the concentration of the antioxidant is about 0.02 mg/ml, about 0.03 mg/ml, about 0.05 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.10 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.15 mg/ml, about 0.18 mg/ml, about 0.20 mg/ml, about 0.22 mg/ml, about 0.25 mg/ml, about 0.27 mg/ml, about 0.30 mg/ml, about 0.40 mg/ml, about 0.45 mg/ml, about 0.50 mg/ml, about 0.60 mg/ml, about 0.80 mg/ml, about 1.2 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml
- an aqueous formulation of a COX-2 inhibitor contains at least one buffering agent, which may maintain the pH of the formulation within an acceptable range as described herein.
- the buffer used is a buffer compatible with parenteral administration in a subject, the pH of which may be adjusted between about 2 and about 8.
- the pH of an aqueous formulation of a COX-2 inhibitor is from about pH 2 to about pH 8, pH 3 to about pH 8, or pH 4 to about pH 8.
- the pH is about pH 4.5, about pH 4.6, about pH 4.8, about pH 5.0, about pH 5.5, about pH 6.2, about pH 6.5, about pH 7.5, or any other suitable pH value from about pH4 to about pH 8.
- the pH of the aqueous formulation is from about pH 5 to about pH 7.0. In some embodiments, the pH is about pH 5.2, about pH 5.5, about pH 5.6, about pH 6.0, about pH 6.4, or any other suitable pH value from about pH 5 to about pH 7.0. In some embodiments, the aqueous formulation of a COX-2 inhibitor has a pH of about 5 to about 6.
- an aqueous formulation of a COX-2 inhibitor contains at least one buffering agent with a pKa from about 4.5 to about 6.5.
- the pKa is about 4.6, about 4.8, about 5.0, about 5.2, about 5.3, about 5.4, about 5.5, about 5.8, about 6.0, about 6.2, about 6.4, or any other suitable pKa from about 4.5 to about 6.5.
- the buffering agent is a pharmaceutically acceptable salt or acid of citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, histidine or other amino acids, gluconate, malate, tryptophan, succinate, formate, propionate, carbonate, or any combination thereof adjusted to an appropriate pH, as described herein, with acid (for example, hydrochloric acid) or base (for example, sodium hydroxide).
- acid for example, hydrochloric acid
- base for example, sodium hydroxide
- the amount % (w/w) of the buffering agent in the solid or lyophilized formulation of the COX-2 inhibitor prior to reconstitution is about 0.05% (w/w) to about 2% (w/w).
- the amount % (w/w) of the buffering agent lyophilized form is about 0.08% (w/w), about 0.10% (w/w), about 0.15% (w/w), about 1.0% (w/w), about 1.3% (w/w), about 1.5% (w/w), about 1.7% (w/w), about 0.20% (w/w), about 0.22% (w/w), about 0.25% (w/w), about 0.26% (w/w), about 0.27% (w/w), about 0.28% (w/w), about 0.30% (w/w), about 0.35% (w/w), about 0.40% (w/w), about 0.50% (w/w), about 0.60% (w/w), about 0.70% (w/w), about 0.80% (w/w/w), about
- the concentration of the buffering agent in an aqueous formulation of a COX-2 inhibitor prior to administration ranges from about 0.01 mg/ml to about 10 mg/ml.
- the concertation is about 0.02 mg/ml, about 0.03 mg/ml, about 0.05 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.10 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.15 mg/ml, about 0.30 mg/ml, about 0.5 mg/ml, about 0.8 mg/ml, about 1.2 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 5.0 mg/ml, about 6.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 9 mg/ml, about 9.5 mg/ml, or any other suitable
- the buffering agent helps prevent formation of an oxidation product of rofecoxib, including 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione and/or 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.
- the buffering agent reduces the formation of 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione and/or 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone by 25%, 50%, or 75% or more.
- an aqueous formulation of a COX-2 inhibitor also contains one or more isotonicity agents, which may maintain the osmolality of the formulation in a range that is physiologically compatible.
- the osmolality of the formulation is physiologically compatible with an intravenous administration of the inhibitor.
- the osmolality of the formulation is about 230 mOsm/L to about 420 mOsm/L.
- the osmolality is about 240 mOsm/L, about 250 mOsm/L, about 260 mOsm/L, about 270 mOsm/L, about 276 mOsm/L, about 290 mOsm/L, about 300 mOsm/L, about 305 mOsm/L, about 310 mOsm/L, about 320 mOsm/L, about 350 mOsm/L, about 375 mOsm/L, about 400 mOsm/L or any other suitable osmolality from about 240 mOsm/L to about 420 mOsm/L.
- the osmolality of the aqueous formulation is about 276 mOsm/L to about 320 mOsm/L. In some embodiments, the osmolality of the formulation is about 290 mOsm/L, about 295 mOsm/L, about 300 mOsm/L, about 305 mOsm/L, about 310 mOsm/L, about 315 mOsm/L, or any other suitable osmolality from about 276 mOsm/L to about 320 mOsm/L. In one embodiment, the osmolality of the aqueous formulation is about 200 mOsm/L-400 mOsm/L.
- Suitable agents for adjusting the isotonicity of the aqueous formulations of COX-2 inhibitors include, but are not limited to, mannitol, sorbitol, glycerol, sucrose, glucose, dextrose, levulose, fructose, lactose, polyethylene glycols 400 to 4000, phosphates, sodium chloride, potassium chloride, calcium chloride, calcium glucono-glucoheptonate, dimethyl sulfone.
- the isotonicity agent is mannitol.
- the isotonic agent is sodium chloride.
- the amount % (w/w) of the isotonicity agent in the solid or lyophilized form of the COX-2 inhibitor formulation prior to reconstitution is about 5% (w/w) to about 95% (w/w). In some embodiments, the amount % (w/w) of the isotonicity agent is about 10% (w/w), about 15% (w/w), about 20% (w/w), about 25% (w/w), about 30% (w/w), about 35% (w/w), about 40% (w/w), about 45% (w/w), about 50% (w/w), about 55% (w/w), about 60% (w/w), about 65% (w/w), about 70% (w/w), about 72% (w/w), about 74% (w/w), about 76% (w/w), about 78% (w/w), about 79% (w/w), about 80% (w/w), about 81% (w/w), about 82% (w/w), about 84% (w/w), about 86% (w/w), about
- the amount of isotonicity agent % (w/w) is about 65% (w/w) to about 85% (w/w). In some embodiments, the amount of isotonicity agent % (w/w) is about 79%.
- the concentration of the isotonicity agent in an aqueous formulation of a COX-2 inhibitor prior to administration ranges from about 1.0 mg/ml to about 150 mg/ml.
- the concentration of the isotonicity agent is about 1.0 mg/ml, about 2.0 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 4.5 mg/ml, about 5.0 mg/ml, about 8.0 mg/ml, about 12 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 32 mg/ml, about 35 mg/ml, about 37 mg/ml, about 38 mg/ml, about 40 mg/ml, about 50 mg/ml, about 60 mg/ml, about 75 mg/ml, about 80 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 110 mg/ml,
- the aqueous formulation does not include one or more of the following excipients: ethyl alcohol, glycerin, glyceryl monocaprylate, L-menthol, lauroyl polyoxyl-32 glycerides, medium chain triglycerides, monoammonium glycyrrhizinate, peppermint flavor, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, propyl gallate, or sucralose.
- excipients ethyl alcohol, glycerin, glyceryl monocaprylate, L-menthol, lauroyl polyoxyl-32 glycerides, medium chain triglycerides, monoammonium glycyrrhizinate, peppermint flavor, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, propyl gallate, or sucralose.
- compositions described herein can also be administered in combination with other therapeutic reagents.
- additional therapeutic agents include, but are not limited to, analgesics, antipyretics, or anti-inflammatory agents.
- other agents do not have to be administered in the same pharmaceutical composition as the COX-2 inhibitor, and may, because of different physical and chemical characteristics, be administered by different routes.
- the therapeutic agent may be administered concurrently (for example, simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the severity of pain experienced by the patient, the nature of the disease, disorder, or condition, the condition, and the actual choice of compounds used.
- dosages of the compounds to be co-administered with an aqueous formulation of the COX-2 inhibitor will vary depending on the type of co-drug employed, on the amount of pain experienced by the patient, the risk for addiction, the disease or condition being treated among other factors.
- the aqueous formulation of a COX-2 inhibitor provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially.
- the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified intravenous form, or in multiple forms (by way of example only, either as a single intravenous formulation, as multiple intravenous formulations, or as intravenous formulation and a pill). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than 1 minute to less than 12 hours. In some embodiments, the timing between the multiple doses is from between about 1 minute to about 6 hours, or about 1 minute and about 3 hours, or about 1 minute and about 1 hour. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.
- the pharmaceutical agents which make up the combination therapy disclosed herein may be a combined dosage form (i.e., a combined IV formulation) or in separate dosage forms intended for substantially simultaneous administration.
- the pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration.
- the two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents.
- the time period between the multiple administration steps may range from a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent.
- the compounds described herein and combination therapies can be administered before, during or after the occurrence of a fever or painful condition, and the timing of administering the composition containing a compound can vary.
- the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions (e.g., body aches and chills following chemotherapy treatment) or diseases in order to prevent the occurrence of the disease or condition.
- the compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
- the administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, preferably within the first 48 hours of the onset of the symptoms, more preferably within the first 6 hours of the onset of the symptoms, and most preferably within 3 hours of the onset of the symptoms.
- intravenous formulations of the pharmaceutical compositions described herein are in the form of a powder to be reconstituted in solution under sterile conditions prior to administration.
- the powder is a lyophilization product of a solution described herein.
- the intravenous formulations are provided as sterile solutions ready for administration.
- the intravenous formulations are in a concentrated form and ready for administration following dilution with a solution.
- Appropriate containers for storage and transport of the pharmaceutical compositions described herein include, but are not limited to, vials, bags, bottles, ampules, or any suitable containers for intravenous formulations known in the art.
- the pharmaceutical compositions disclosed herein can be prepared and administered in dose units.
- Liquid dose units are vials or ampoules for injection or other parenteral administration.
- the vial or ampule contains 50 ml, 60 ml, 70 ml, 80, ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml of a COX-2 inhibitor solution.
- the vial or ampule contains 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg or more of a water insoluble COX-2 inhibitor.
- the pharmaceutical composition described herein is diluted with a water-based solution to create an infusate that is ready for administration.
- a water-based solution to create an infusate that is ready for administration.
- concentrated compositions can be used.
- the concentrate can contain 50 ⁇ g/ml, 100 ⁇ g/ml, 150 ⁇ g/ml, 200 ⁇ g/ml, 250 ⁇ g/ml, 300 ⁇ g/ml, 350 ⁇ g/ml, 400 ⁇ g/ml, 450 ⁇ g/ml, 500 ⁇ g/ml or more of the water insoluble COX-2 inhibitor.
- a bag, vial, bottle, or other container is partially filled with the concentrated pharmaceutical composition and a pharmacist or healthcare provide adds 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, 200 ml or more of a diluent to the container prior to intravenous administration.
- a bag, vial, bottle, or other container with the concentrated pharmaceutical composition is provided and a pharmacist or healthcare provider removes 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, or 200 ml of the concentrate and adds it to 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, 200 ml or more of a diluent to create
- an empty bag, vial, bottle, or other container is provided and a pharmacist or healthcare provider adds 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml or more of diluent and 5 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml or more of concentrate to create an infusate.
- the infusate comprises 15 ml, 20 ml, 25 ml, 30 ml, 35 ml, 40 ml, 45 ml, 50 ml, 55 ml, 60 ml, 65 ml, 70 ml, 75 ml, 80 ml, 85 ml, 90 ml, 95 ml, 100 ml or more of the concentrate and diluent.
- the pharmaceutical composition described herein may be a lyophilized pharmaceutical composition comprising a lyophilization product of the aqueous formulations described herein.
- the lyophilization product may comprise 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg or more of a water insoluble COX-2 inhibitor.
- the lyophilization product may be reconstituted in solution under sterile conditions prior to administration.
- the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is an oral suspension. In some embodiments, the pharmaceutical composition is an oral solution. In some embodiments, the pharmaceutical composition is a solution suitable for injection.
- the oral solution may further contain at least one flavoring agent or taste masking agent.
- flavoring agents/taste masking agents natural and synthetic flavoring liquids such as volatile oils, synthetic flavor oils, flavoring aromatic oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof.
- volatile oils include spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, menthol, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice oil, oil of sage, mace extract, oil of bitter almond, and cassia oil.
- artificial, natural or synthetic flavors including fruit flavors such as vanilla, and citrus oils including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, banana and other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral, i.e., alphocitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin), bubble gum flavor, mixtures thereof and the like.
- aldehydes and esters such as benzaldehyde
- the oral solution may further contain a sweetener.
- a sweetener such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof, saccharin and its various salts such as the sodium or calcium salt; cyclamic acid and its various salts such as the sodium salt; the dipeptide sweeteners such as aspartame, acesulfame K, and other sweeteners like magnasweet, sucralose, mixtures thereof and the like.
- the subject matter disclosed herein provides a method of treating pain, fever, or inflammation in a subject in need thereof, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject. In some embodiments, the subject matter disclosed herein provides a method of managing mild to moderate pain in a subject, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject. In some embodiments, the subject matter disclosed herein provides a method of managing moderate to severe pain, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject with adjunctive opioid analgesics.
- the subject matter disclosed herein provides a method of reducing fever in a subject, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject.
- the subject matter disclosed herein provides a method of short-term ( ⁇ 5 days) management of moderately severe acute pain, which requires analgesia at the opioid level in a subject, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject.
- aqueous formulations of the water insoluble COX-2 inhibitors described herein can be used for reducing pain conditions including, but not limited to, acute nociceptive pain, acute neuropathic pain, postoperative pain, lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, opioid-resistant pain, visceral pain, surgical pain, procedural pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post-partum pain, headache, muscular aches, backache, arthritis pain, the common cold, toothache, dental pain, osteoarthritis pain, menstrual pain, menstrual cramps, migraine, and genitourinary tract-related pain including cystitis.
- the aqueous formulation is administered prior to the onset of pain or a pain inducing condition or stimulus, for example prior to a surgical operation.
- the aqueous formulations of water insoluble COX-2 inhibitors described herein are used to reduce fever, including, but not limited to, fever due to infections, drug reactions, allergic reactions, transfusion reactions, stroke, surgery, heat stroke, rheumatic diseases, cancer, or fever of unknown origin.
- the aqueous formulations described herein are administered to a patient undergoing a dental procedure.
- a single dose formulation of a water insoluble COX-2 inhibitor contains 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- the concentration of a water insoluble COX-2 inhibitor in an aqueous formulation is about 0.001% (w/v) to about 0.07% (w/v). In some embodiments, the concentration (w/v) of a COX-2 inhibitor in an aqueous formulation is about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% or any other suitable concentration. In one embodiment, the concentration of the COX-2 inhibitor is from about 0.01% to about 0.03% (w/v).
- the volume of aqueous formulation administered can vary from about 1 ml to about 200 ml.
- the volume of an aqueous formulation is about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 10 ml, 20 ml, 25 mL, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80, ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 180 ml, or any suitable volume of the aqueous formulation.
- the volume of the aqueous formulation is about 75 ml to about 125 ml. In another embodiment, the volume is about 40 ml to about 75 ml. In yet another embodiment, the volume of the aqueous formulation is about 100 ml.
- the dosing regimen of the pharmaceutical composition described herein is a once daily administration. In some embodiments, the dosing regimen of the pharmaceutical composition described herein is multiple times per day. In some embodiment, the dosing regimen of the pharmaceutical composition described herein is twice per day, three times per day, four times per day, five times per day, or six times per day. In some embodiments, the dosing regimen is three times per day of intravenous administration of the pharmaceutical composition. In some embodiments, the dosing regimen is four times per day of intravenous administration of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 5 mg to 15 mg of rofecoxib and is administered in a 100 ml infusate three to four times per day.
- An aqueous formulation of a water insoluble COX-2 inhibitor can be administered in an interval to allow for the administration of about 10 mg to about 200 mg in a 24 hour period. In some embodiments, the aqueous formulation is administered in an interval sufficient to allow for the administration of about 20 mg to 100 mg in a 24 hour period. In some embodiments, the aqueous formulation is administered between 1 to 6 times every twenty-four hours. In some embodiments, the frequency of administration is not greater than once every four hours.
- the aqueous formulation of a water insoluble COX-2 inhibitor is dosed so as to provide less than about 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg over a 24-hour period.
- the aqueous formulation is dosed three to six times in a 24-hour period.
- the aqueous formulation is dosed three times in a 24-hour period.
- the aqueous formulation is dosed four times in a 24-hour period.
- the aqueous formulation is dosed five times in a 24-hour period.
- the aqueous formulation is dosed six times in a 24-hour period.
- the aqueous formulation is dosed seven times in a 24-hour period.
- the aqueous formulation is dosed eight times in a 24-hour period.
- the infusion time of the intravenous formulation of the COX-2 inhibitor is about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 45 min, about 50 min, about 60 min or more. In some embodiments, the infusion time is between 10 min and 30 min. In some embodiments, the infusion time ranges from about 1 minute to about 1 hour. In some embodiments, the infusion time is about 5 minutes, about 10 minutes, about 11 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, or any other suitable administration time from about 1 minute to about 1 hour. In some embodiments, the amount of time required for administration of the intravenous formulation ranges from about 5 minutes to about 45 minutes, or about 5 minutes to about 30 minutes, or about 5 minutes to about 15 minutes.
- the aqueous formulation of a COX-2 inhibitor is administered to a subject within about 12 hours after a surgical intervention, within 11 hours, 10 hours, 9 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hours, 45 minutes, 30 minutes 15 minutes, 5 minutes, or any period within about 12 hours following a surgical intervention.
- a subject is administered the aqueous formulation prior to a surgical intervention, about 4 hours or less prior to the surgical intervention, about 3 hours, 2 hours, 1 hours, 30 minutes, 15 minutes or during the surgical intervention itself.
- compositions described herein include the COX-2 inhibitor rofecoxib (also known as TRM-201) in a solution comprising hydroxypropyl ⁇ -cyclodextrin (HPbCD) or sulfobutyl ether- ⁇ -cyclodextrin (e.g., Captisol®) and water as shown in FIGS. 1 and 3 and Table 1 below:
- COX-2 inhibitor rofecoxib also known as TRM-201
- HPbCD hydroxypropyl ⁇ -cyclodextrin
- Captisol® sulfobutyl ether- ⁇ -cyclodextrin
- the vehicle composition includes a cyclodextrin and water in a 15/85 (w/v) ratio.
- addition of a second solubilizing agent to the vehicle composition increases solubility of the water insoluble COX-2 inhibitor.
- addition of a second solubilizing agent increases the solubility of the water insoluble COX-2 inhibitor to 110 ⁇ g/ml, 115 ⁇ g/ml, 120 ⁇ g/ml, 130 ⁇ g/ml, 140 ⁇ g/ml or greater.
- the second solubilizing agent is a co-solvent helper such as ethanol, PS 20, or PS 80. In some embodiments, the second solubilizing agent is Soluplus®. In some embodiments, addition of the second solubilizing agent increases the solubility of the water insoluble COX-2 inhibitor to 120 ⁇ g/ml or greater.
- TRM-201 solubility Vehicle # Vehicle Composition ( ⁇ g/mL) @ t 24 h V204 5/15/80 (v/w/v) DMSO / HPbCD / Water 75.5 V205 5/15/80 (v/w/v) EtOH / HPbCD / Water 79.9 V206 5/15/80 (w/w/v) Kolliphor HS 15 / HPbCD / Water 83.1 V207 5/15/80 (w/w/v) Poloxamer 188 / HPbCD / Water 92.8 V208 5/15/80 (v/w/v) PS 20 / HPbCO / Water 88.5 V209 5/15/80 (v/w/v) PS 80 / HPbCO / Water 100 V210 5/15/80 (w/w/v) Soluplus / HPbCD / Water 111.2 V211 5/5/15/75 (w/w/w/v) Soybean oil/ Span 40 / HPbCD / Water
- a 5/15/80 (w/w/v) mixture of Soluplus®/Captisol/Water (V218) achieved a solubility of rofecoxib of 140.5 ⁇ g/ml at t 24 h
- a 20/80 (w/v) mixture of Captisol/Water (V174) achieved a solubility of rofecoxib of 113 ⁇ g/ml at t 24 h.
- addition of a second solubilizing agent to the pharmaceutical composition increases the solubility of a water insoluble COX-2 inhibitor by 5%, 10%, 15%, 20%, 25%, 30% or more.
- the pharmaceutical composition described herein includes about 10 ⁇ g/ml of rofecoxib. In some embodiments, the pharmaceutical composition further includes at least one ⁇ -cyclodextrin and water. In some embodiments, the pharmaceutical composition is 10 ⁇ g/ml of rofecoxib in ⁇ -cyclodextrin and water.
- the pharmaceutical composition is in a 100 ml “ready to use” form.
- the pharmaceutical composition is concentrated and has to be diluted to a 100 ml volume prior to use to create the infusate.
- the 100 ml infusate is intravenously administered to a subject 3-4 times per day to treat acute pain in a surgical setting, for example to treat post-operative pain.
- compositions e.g. oral solution or composition for intravenous administration
- the compositions may comprise any of the following compositions or components as described in FIGS. 1 and 3 and Table 3 below.
- TRM-201 solubility Vehicle # Vehicle Composition ( ⁇ g/mL) @ t 24 h V01 2/98 (v/v) BnOH / Water 9 V02 10/90 (v/v) Corn oil / Water 18 V03 40/60 (v/v) Kolliphor EL/ 294 Water V04 50/50 (v/v) Kolliphor EL / 2055 EtOH V05 10/90 (v/v) DMSO / Water 8 V06 30/70 (v/v) DMA / Water 63 V07 1/99 (v/v) Glyceryl 8 monooleate / Water V08 20% (w/v)HPbCD in water 110 V09 1% (w/v) Lecithin in water 10 V10 20/80 (v/v) NMP / Water 40 V11 20/80 (v/v) Miglyol 812 N / 11 Water V12 1% (w/v) Oleic acid in water 33 V13 10% (w/v)
- the subject matter disclosed herein relates to oral solution formulations of water insoluble COX-2 inhibitors.
- the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib.
- the water insoluble COX-2 inhibitor is rofecoxib.
- the subject matter disclosed herein relates to oral solution formulations of rofecoxib.
- the subject matter described herein relates to a single-dose, open-label, phase I, two-period crossover pharmacokinetic study of 17.5-mg doses of TRM-201 (rofecoxib) oral tablets and a solution of TRM-201 administered as an oral solution (TRM-201 OS) to healthy subjects in a fasting state.
- TRM-201 OS To evaluate and compare key pharmacokinetic parameters of the TRM 201 oral tablets and TRM 201 oral solution (TRM-201 OS). Key pharmacokinetic parameters include area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) and observed maximum plasma concentration (C max ).
- the subject matter disclosed herein relates to a single-center, open-label, Phase I, two-period crossover pharmacokinetic (PK) study to assess single oral tablet and single oral solution administrations of TRM-201 in healthy subjects in a fasting state. Twelve heathy subjects who meet eligibility criteria will be randomized to receive one of two treatment sequences that consist of a single oral tablet of TRM-201 and a single oral solution of TRM-201 with the primary objectives of comparing the key PK parameters of the two dosage forms. Subjects will enter the clinic the day before their planned dosing and will remain in the clinic throughout the two-period crossover.
- PK pharmacokinetic
- the maximum duration for each subject's participation in the study is up 35 days: up to 27 days for screening (minus admission day) and 8 in-clinic days.
- the 8 in-clinic days consist of 1 day for check-in and 3 days for each of the two periods plus an additional washout day between Periods 1 and 2.
- TRM-201 An immediate-release tablet that contains rofecoxib. An oral dose of 17.5 mg rofecoxib will be administered in the two-period crossover.
- TRM-201 OS (0.1 mg/mL Rofecoxib Oral Solution): An oral solution consisting of 0.1 mg/mL rofecoxib in 20% Captisol® in 50 mM citrate buffer pH 4.5 at a total dose administration of 17.5 mg of rofecoxib in 175 mL will be administered in the two-period crossover. The total amount of Captisol® to be consumed in the 175 mL oral solution is 35 g.
- Patient population healthy subjects
- TRM-201 Oral tablet 17.5 mg and TRM-201 OS in 20% Captisol®, 17.5 mg in 175 mL
- the subject is 18 to 60 years of age, inclusive, at Screening.
- All female subjects must have a negative pregnancy test at Screening and Check-in.
- Female subjects of childbearing potential must be using an acceptable method of birth control during the study (i.e., diaphragm with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral contraceptives, or abstinence).
- Women who are surgically sterile i.e., hysterectomy, bilateral tubal ligation, bilateral salpingectomy or bilateral oophorectomy
- postmenopausal defined as amenorrhea for 12 consecutive months and documented serum follicle-stimulating hormone level >40 IU/mL [confirmed at Screening] are exempt from the contraception requirement.
- the subject has a body mass index (BMI) at Screening of 18.0 to 32.0 kg/m2, inclusive, with a minimum weight of 47 kg for women and 66 kg for men.
- BMI body mass index
- the subject is not a smoker (or user of e-cigarettes).
- the investigator considers the subject to be in good general health as determined by medical history, clinical laboratory test results, vital sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination findings at Screening and Check-in.
- ECG electrocardiogram
- the subject provides written informed consent.
- the subject has a creatinine level at or below the upper limit of normal.
- the subject has a history of a relevant drug allergy or food allergy/sensitivity (e.g., allergy to rofecoxib or excipients of TRM-201 (including Captisol®-containing products), allergy to other non-steroidal anti-inflammatory drugs (NSAIDs), or gluten intolerance that could preclude consumption of a standard clinic diet).
- a relevant drug allergy or food allergy/sensitivity e.g., allergy to rofecoxib or excipients of TRM-201 (including Captisol®-containing products), allergy to other non-steroidal anti-inflammatory drugs (NSAIDs), or gluten intolerance that could preclude consumption of a standard clinic diet.
- a female subject is pregnant or lactating.
- the subject has a history of intolerance or hypersensitivity to aspirin or any other NSAID.
- the subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at Screening.
- the subject has used any prescription (excluding hormonal birth control) or over the counter medications (OTC) including NSAIDs (e.g., ibuprofen, naproxen, and aspirin) as well as herbal or nutritional supplements, within 14 days (or 5 half-lives, whichever is longer) before the vehicle or study drug dosing.
- NSAIDs e.g., ibuprofen, naproxen, and aspirin
- Subjects may have taken acetaminophen (up to 2 g per day) in the 14 days prior to but not the day before dosing in this study.
- Prescription and OTC medications as well as herbal or nutritional supplements are prohibited throughout the study.
- COVID-19 vaccines are accepted concomitant medications, but subjects are not to receive a COVID vaccination within 72 hours prior to check-in.
- the subject has any clinically significant abnormalities before dosing on Day 1 or has a history of disease, including: uncontrolled or poorly controlled hypertension; asthma or pulmonary disease; major cardiac ischemic symptoms, events, or interventions such as angina pectoris, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, coronary stent or bypass; history of cerebrovascular ischemic events (transient ischemic attack or stroke); major vascular ischemic symptoms such as intermittent claudication or vascular bypass or replacement surgery; significant cardiovascular (CV), gastrointestinal (GI), neurological, endocrine, or renal disease; hepatic impairment; cholecystectomy; other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs; or clinically significant GI events.
- CV cardiovascular
- GI gastrointestinal
- hepatic impairment cholecystectomy
- other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs or clinically significant GI events.
- the subject has a history or presence of any clinically significant abnormality in vital signs, ECG, or laboratory tests, or has any medical or psychiatric condition that, in the opinion of the investigator, may interfere with the study procedures or compromise subject safety (assessed at Screening and Check-in).
- the subject is a cigarette smoker or has used nicotine or nicotine-containing products (e.g., snuff, nicotine patch, nicotine chewing gum, e-cigarettes) within 6 months prior to dosing in this study.
- nicotine or nicotine-containing products e.g., snuff, nicotine patch, nicotine chewing gum, e-cigarettes
- the subject has a history of alcohol abuse or drug addiction within the last year or consumes more than 1 unit (1 unit is equal to approximately 1 ⁇ 2 pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a day. Alcohol is not allowed within 7 days before study drug dosing.
- the subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at Screening.
- the subject is a habitual and heavy coffee drinker (more than 4 cups a day, 28 cups a week).
- the subject is involved in strenuous activity or contact sports within 24 hours prior to dosing in this study.
- the subject has donated blood or blood products within 30 days prior to dosing in this study.
- the subject has received study drug in another investigational study within 30 days (or less than 5 half-lives of the investigational agent) prior to dosing in this study.
- the subject is not suitable for entry into the study, in the opinion of the investigator.
- the subject is an employee or family member of the investigator or clinic staff.
- the subject has evidence of current SARS-CoV-2 infection.
- the subject has poor venous access that limits phlebotomy.
- the subject has a creatinine level at or below the upper limit of normal.
- Safety and tolerability assessments will include monitoring and recording of adverse events (AEs), serious adverse events (SAEs), clinical laboratory assessments (hematology, serum chemistry, and urinalysis), vital sign measurements, 12-lead ECG assessments, and physical examination findings.
- AEs adverse events
- SAEs serious adverse events
- clinical laboratory assessments hematology, serum chemistry, and urinalysis
- vital sign measurements 12-lead ECG assessments, and physical examination findings.
- AESIs Adverse events of special interest
- Plasma samples will be analyzed for TRM-201 using a validated method.
- the obtained plasma concentration-time data for TRM-201 will be analyzed using appropriate non compartmental techniques to obtain estimates of the following parameters, where appropriate and possible: Tlag, Tmax, Cmax, AUC0-24, AUC0-last, AUC0-inf, AUCextrap, t1 ⁇ 2, lambda-z, CL/F, Vz/F.
- Baseline demographic and background variables will be summarized overall for all subjects. The number of subjects who enroll in the study and the number and percentage of subjects who complete the study will be presented. The frequency and percentage of subjects who withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, will also be summarized. Data will be listed in data listings.
- PK endpoints (both parameters and concentrations) will be summarized using descriptive statistics (number of subjects, mean, SD, median, minimum, maximum, geometric mean, geometric CV(%) and geometric SD). Data will be provided as data listings. Relative bioavailability will be estimated from the geometric mean ratio of Cmax, AUClast, and AUC0-inf (oral tablet versus oral solution) derived from a 2-period crossover model analysis of natural log transformed values. The associated 90% confidence interval will also be provided.
- FIG. 4 shows C max values for the tablet and oral solution (OS) formulations of rofecoxib (TRM-201).
- FIG. 4 shows that the C max values for almost every subject is higher for the oral solution formulation than for the tablet formulation of rofecoxib. This leads to a higher geometric mean value of 345.3 ng/ml for C max following oral solution administration compared to 289.1 ng/ml for C max following administration of the tablet formulation.
- FIG. 5 shows AUC for the tablet and oral solution (OS) formulations of rofecoxib (TRM-201).
- FIG. 5 shows that the AUC is equivalent for the tablet formulation of rofecoxib with a geometric mean AUC at 3817.3 ng*h/ml and the oral solution formulation of rofecoxib with a geometric mean AUC at 3840.2 ng*h/ml.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Described herein are compositions and methods for treatment with aqueous formulations of water insoluble COX-2 inhibitors and a solubilizing agent.
Description
- This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/106,571, filed on Oct. 28, 2020, the content of which is hereby incorporated by reference in its entirety.
- All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application.
- This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.
- Analgesics to control postoperative pain can be administered immediately prior to surgery (preoperatively), during surgery (intraoperatively), after surgery (postoperatively), or following hospital discharge via a prescription. Commonly used drug classes include opioids, acetaminophen, nonselective NSAIDs, and local anesthetics. Currently, the market for intravenously administered analgesics is dominated by two agents: IV ketorolac (TORADOL) and IV acetaminophen (OFIRMEV). IV ketorolac is widely used because of its strong efficacy profile, but it carries several important limitations, including a significant risk of serious gastrointestinal (GI) bleeds, an indication that is limited to short-term (<5 days) use in adults only, and a contra-indication for pre-operative use, due to its effect on platelet aggregation. IV acetaminophen, on the other hand, is recognized as safer than IV ketorolac, but is limited in use due to its modest efficacy at treating pain. NSAIDs have pain-relieving, antipyretic and anti-inflammatory properties, are proven to be effective following day surgery and minor surgery, and have an opiate-sparing effect after more major surgery. However, a major concern regarding the use of conventional NSAIDs postoperatively is the possibility of bleeding from both the operative site (because of the inhibition of platelet aggregation) and from the upper GI tract (especially in patients stressed by surgery, the elderly, frail, or dehydrated). There is a significant but unmet need for intravenously administered drugs that combine the pain-relieving properties of NSAIDs without these adverse effects, especially to control postoperative pain.
- COX-2 inhibitors are a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs) that have been shown to be highly effective in treating conditions such as acute pain, and may be administered to patients with a high risk of operative site bleeding, upper GI bleeding or those with a history of peptic ulcer. Few, if any, COX-2 selective NSAIDs are available in a formulation that is suitable for use in an intravenous or other parenteral administration, due to the fact that they are insoluble or practically insoluble in water. These water insoluble COX-2 inhibitors include rofecoxib, etoricoxib, and celecoxib. Described herein are aqueous formulations of water insoluble COX-2 inhibitors suitable for oral or intravenous or other parenteral administration.
- In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and c) a solubilizing agent, wherein the solubility of the water insoluble COX-2 inhibitor in the solution is more than 10 μg/ml.
- In some embodiments, the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent.
- In some embodiments, said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted prior to administration.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the effective amount of the water insoluble COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the concentration % (w/v) of the water insoluble COX-2 inhibitor in the solution is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration. In some embodiments, the volume of the solution is selected from the group consisting of about 5 mL, about 10 ml, about 20 ml, about 25 mL, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume. In some embodiments, the solubility of the water insoluble COX-2 inhibitor in the solution is more than 20 μg/ml, more than 30 μg/ml, more than 40 μg/ml, more than 50 μg/ml, more than 60 μg/ml, more than 70 μg/ml, more than 80 μg/ml, more than 90 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ml, more than 130 μg/ml, more than 140 μg/ml, or more than 150 μg/ml.
- In some embodiments, said composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, said composition is suitable for intravenous administration to a subject.
- In certain aspects, the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a lyophilization product of any of the pharmaceutical compositions described herein.
- In certain aspects, the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising parenterally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a COX-2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and c) a solubilizing agent.
- In some embodiments, the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib.
- In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent. In some embodiments, said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the effective amount of the COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the concentration % (w/v) of the COX-2 inhibitor in an aqueous formulation is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration. In some embodiments, the volume of an aqueous formulations of the COX-2 inhibitor is selected from the group consisting of about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 10 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume. In some embodiments, the solubility of the COX-2 inhibitor is enhanced to more than 10 μg/ml, more than 20 μg/ml, more than 30 μg/ml, more than 40 μg/ml, more than 50 μg/ml, more than 60 μg/ml, more than 70 μg/ml, more than 80 μg/ml, more than 90 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ml, more than 130 μg/ml, more than 140 μg/ml, or more than 150 μg/ml. In some embodiments, said composition is administered as part of a combination therapy with at least one other therapeutic agent.
- In certain aspects, the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof and a solubilizing agent, wherein the lyophilized pharmaceutical composition is a produced by lyophilizing a pharmaceutical composition comprising an aqueous formulation comprising water, a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and a solubilizing agent.
- In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent. In some embodiments, the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- In some embodiments, the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the 3-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the pharmaceutical composition comprises an effective amount of the COX-2 inhibitor in a single dose, wherein the effective amount is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the pharmaceutical composition has a volume of the oral solution selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume. In some embodiments, the pharmaceutical composition the oral solution comprises of about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
- In some embodiments, the pharmaceutical composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, the pharmaceutical composition is suitable for oral administration to a subject.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma AUC0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a plasma AUC0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma Cmax from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma Cmax is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a Cmax of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
- In certain aspects, the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent. In some embodiments, the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- In some embodiments, the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the 3-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the method comprises an effective amount of the COX-2 inhibitor in a single dose selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the oral solution has a volume selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume. In some embodiments, the oral solution comprises about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib. In some embodiments, the composition is administered as part of a combination therapy with at least one other therapeutic agent.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma AUC0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a plasma AUC0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma Cmax from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma Cmax is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a Cmax of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
-
FIG. 1 shows results summary for screening vehicle compositions 169-203. -
FIG. 2 shows results summary for screening vehicle compositions 204-219. -
FIG. 3 shows results summary for screening vehicle compositions 135-168. -
FIG. 4 shows Cmax values for the tablet and oral solution (OS) formulations of rofecoxib. -
FIG. 5 shows AUC for the tablet and oral solution (OS) formulations of rofecoxib. - The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
- As used herein, “solubilizing agent” refers to, but is not limited to, a cyclodextrin, a polyethylene glycol, a protic solvent, a dipolar aprotic solvent, a lipid, or a surfactant.
- As used herein, “cyclodextrin” refers to a cyclic oligosaccharide. Cyclodextrin includes, but is not limited to, the compounds known as β-cyclodextrin, α-cyclodextrin, and γ-cyclodextrin, and derivatives thereof.
- As used herein, a “water insoluble COX-2 inhibitor” includes any COX-2 inhibitor which is insoluble or practically insoluble in water. Water insoluble COX-2 inhibitor includes rofecoxib, etoricoxib, celecoxib, and pharmaceutically acceptable salts, esters, or co-crystals thereof.
- As used herein, “treat,” “treating or “treatment” include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
- As used herein, “effective amount” refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome. In some instances, an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
- As used herein, “administer,” “administering,” “administration,” refer to the methods used to enable delivery of a pharmaceutical compositions to the targeted location of biological action.
- As used herein, “acceptable” with respect to a pharmaceutical composition refers to the composition having no persistent detrimental effect on the general health of a subject being treated.
- As used herein, “antioxidant” refers to a pharmaceutical compound that prevents oxygen or oxygen-derived free radicals from interacting with other substances. The general function of antioxidants in compositions is to minimize or distort the oxidative processes that occur with some pharmaceutical compounds or excipients upon exposure to oxygen or in the presence of free radicals.
- As used herein, “co-administration” means the administration of two agents (e.g. concomitantly or sequentially) in any manner in which the pharmacological effects of both are manifest in the subject at the same time. Concomitant administration does not require that both agents be administered in a single pharmaceutical composition, in the same dosage form, or by the same route of administration. The effects of both agents need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive.
- As used herein, the term “subject” refers to a vertebrate animal. In one embodiment, the subject is a mammal or a mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals.
- As used herein, the term “patient” refers to a human or animal.
- As used herein, the term “mammal” includes, but is not limited to, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In one embodiment, the mammal is a human.
- As used herein, “pain” refers to all types of pain, including, but not limited, to nociceptive pain, neuropathic pain, post-operative pain, lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, migraine, and genitourinary tract-related pain including cystitis.
- Non-Limiting Embodiments of the Compositions
- In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and c) a solubilizing agent, wherein the solubility of the water insoluble COX-2 inhibitor in the solution is more than 10 μg/ml.
- In some embodiments, the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent.
- In some embodiments, said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted prior to administration.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the effective amount of the water insoluble COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the concentration % (w/v) of the water insoluble COX-2 inhibitor in the solution is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration. In some embodiments, the volume of the solution is selected from the group consisting of about 5 mL, about 10 ml, about 20 ml, about 25 mL, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume. In some embodiments, the solubility of the water insoluble COX-2 inhibitor in the solution is more than 20 μg/ml, more than 30 μg/ml, more than 40 μg/ml, more than 50 μg/ml, more than 60 μg/ml, more than 70 μg/ml, more than 80 μg/ml, more than 90 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ml, more than 130 μg/ml, more than 140 μg/ml, or more than 150 μg/ml.
- In some embodiments, said composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, said composition is suitable for intravenous administration to a subject.
- In certain aspects, the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a lyophilization product of any of the pharmaceutical compositions described herein.
- In certain aspects, the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising parenterally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an aqueous solution comprising: a) water, b) a COX-2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and c) a solubilizing agent.
- In some embodiments, the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib.
- In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the composition further comprises at least one isotonic agent. In some embodiments, said composition is a reconstituted lyophile. In some embodiments, said pharmaceutical composition is diluted.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the effective amount of the COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the concentration % (w/v) of the COX-2 inhibitor in an aqueous formulation is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration. In some embodiments, the volume of an aqueous formulations of the COX-2 inhibitor is selected from the group consisting of about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 10 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume. In some embodiments, the solubility of the COX-2 inhibitor is enhanced to more than 10 μg/ml, more than 20 μg/ml, more than 30 μg/ml, more than 40 μg/ml, more than 50 μg/ml, more than 60 μg/ml, more than 70 μg/ml, more than 80 μg/ml, more than 90 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ml, more than 130 μg/ml, more than 140 μg/ml, or more than 150 μg/ml. In some embodiments, said composition is administered as part of a combination therapy with at least one other therapeutic agent.
- In certain aspects, the subject matter disclosed herein provides a lyophilized pharmaceutical composition comprising a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof and a solubilizing agent, wherein the lyophilized pharmaceutical composition is a produced by lyophilizing a pharmaceutical composition comprising an aqueous formulation comprising water, a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and a solubilizing agent.
- In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent. In some embodiments, the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- In some embodiments, the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the 3-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the pharmaceutical composition comprises an effective amount of the COX-2 inhibitor in a single dose, wherein the effective amount is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the pharmaceutical composition has a volume of the oral solution selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume. In some embodiments, the pharmaceutical composition the oral solution comprises of about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
- In some embodiments, the pharmaceutical composition is administered as part of a combination therapy with at least one other therapeutic agent. In some embodiments, the pharmaceutical composition is suitable for oral administration to a subject.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma AUC0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a plasma AUC0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma Cmax from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma Cmax is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a Cmax of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
- In certain aspects, the subject matter disclosed herein provides a method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an oral solution comprising: a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and b) a solubilizing agent. In some embodiments, the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
- In some embodiments, the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the composition further comprises at least one co-solvent helper. In some embodiments, the composition further comprises at least one antioxidant. In some embodiments, the composition further comprises at least one buffering agent. In some embodiments, the pharmaceutical composition is diluted prior to administration.
- In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof. In some embodiments, the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the 3-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the method comprises an effective amount of the COX-2 inhibitor in a single dose selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg. In some embodiments, the oral solution has a volume selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume. In some embodiments, the oral solution comprises about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib. In some embodiments, the composition is administered as part of a combination therapy with at least one other therapeutic agent.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma AUC0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a plasma AUC0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
- In some embodiments, the oral solution comprises rofecoxib and achieves a geometric mean plasma Cmax from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age. In some embodiments, the geometric mean plasma Cmax is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml. In some embodiments, the oral solution comprising rofecoxib achieves a Cmax of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
- Pharmaceutical Compositions
- Described herein are aqueous formulations of water insoluble COX-2 inhibitors and methods of treatment or prevention of pain, fever, or inflammation, including postoperative pain, by administering a pharmaceutical composition including a water insoluble COX-2 inhibitor and one or more solubilizing agents. In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the COX-2 inhibitor is rofecoxib. In some embodiments, the COX-2 inhibitor is etoricoxib. In some embodiments, the COX-2 inhibitor is celecoxib.
- In some embodiments, the pharmaceutical compositions described herein comprise an aqueous solution including water, a solubilizing agent, and a water insoluble COX-2 inhibitor. In some embodiments, the solubilizing agent is a cyclodextrin. In some embodiments, the solubilizing agent comprises a polyethylene glycol. Exemplary embodiments of polyethylene glycol include, but are not limited to, PEG300 and PEG400. In some embodiments, the solubilizing agent is Soluplus®. In some embodiments, the solubilizing agent is a protic solvent. In some embodiments, the solubilizing agent is a dipolar aprotic solvent, for example DMSO or DMF. In some embodiments, the solubilizing agent is a lipid. In some embodiments, the solubilizing agent is soybean oil. In some embodiments, the solubilizing agent is a surfactant, for example Kolliphor®, polysorbate 20 (PS 20), or polysorbate 80 (PS 80). In some embodiments, the solubilizing agent is a co-solvent helper such as ethanol. In some embodiments, pharmaceutical compositions may include more than one solubilizing agent. In one embodiment, the solubilizing agents include a cyclodextrin and a polyethylene glycol. In another embodiment, the solubilizing agents include a cyclodextrin and Soluplus®. In some embodiments, the pharmaceutical compositions are suitable for administration to a subject. In some embodiments, the pharmaceutical compositions are suitable for oral or parenteral administration to a human. In some embodiments, the pharmaceutical compositions are suitable for intravenous administration to a human.
- In some embodiments, the pharmaceutical compositions described herein are in a dose unit that is “ready to use” for injection or other parenteral administration. In some embodiments, the pharmaceutical compositions described herein are diluted with a sterile solution prior to administration. In some embodiments, the pharmaceutical compositions described herein are formed by reconstituting a lyophilization product (e.g., a powder) with a sterile solution.
- In some embodiments, the cyclodextrin is a cyclic oligosaccharide. In some embodiments, the cyclodextrin is a β-cyclodextrin or a derivative thereof. In some embodiments, the cyclodextrin is an α-cyclodextrin or a derivative thereof. In some embodiments, the cyclodextrin is a γ-cyclodextrin or a derivative thereof.
- In some embodiments, the β-cyclodextrin derivative is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5. In some embodiments, the hydroxypropyl-β-cyclodextrin is Cavasol®. In some embodiments, the β-cyclodextrin derivative is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0. In some embodiments, the sulfobutyl ether-β-cyclodextrin is Captisol®.
- In some embodiments, the “water insoluble COX-2 inhibitor” is a COX-2 inhibitor which is insoluble or practically insoluble in water. In some embodiments the water insoluble COX-2 inhibitor is rofecoxib. In some embodiments the water insoluble COX-2 inhibitor is etoricoxib. In some embodiments the water insoluble COX-2 inhibitor is celecoxib. In some embodiments the water insoluble COX-2 inhibitor has a solubility of less than 10 μg/ml.
- In some embodiments, the total amount of the one or more solubilizing agent in the aqueous solution is about 5% (w/v), 10% (w/v), 15% (w/v), 20% (w/v), 25% (w/v), 30% (w/v), 35% (w/v), 40% (w/v/), 45% (w/v), 50% (w/v), 55% (w/v), 60% (w/v), 70% (w/v), 80% (w/v) or more. In some embodiments, the total amount of solubilizing agent(s) in the aqueous solution is about 5% (v/v), 10% (v/v), 15% (w/v), 20% (v/v), 25% (v/v), 30% (v/v), 35% (v/v), 40% (v/v/), 45% (v/v), 50% (v/v), 55% (v/v), 60% (v/v), 70% (w/v), 80% (v/v) or more.
- In some embodiments, the total amount of the solubilizing agent(s) in the aqueous formulation ranges from 5-10% (w/v), 10-15% (w/v), 15-20% (w/v), 20-25% (w/v), 25-30% (w/v), 30-35% (w/v), 35-40% (w/v), 40-45% (w/v), 45-50% (w/v), 50-55% (w/v), or 55-60% (w/v), or 60-80% (w/v). In some embodiments, the total amount of solubilizing agent(s) in the aqueous formulation ranges from 5-10% (v/v), 10-15% (v/v), 15-20% (v/v), 20-25% (v/v), 25-30% (v/v), 30-35% (v/v), 35-40% (v/v), 40-45% (v/v), 45-50% (v/v), 50-55% (v/v), 55-60% (v/v), or 60-80% (v/v).
- In some embodiments, the subject matter described herein relates to enhanced solubility of water insoluble COX-2 inhibitors. In some embodiments, the solubility of COX-2 inhibitors is enhanced to more than 10 μg/ml, more than 20 μg/ml, more than 30 μg/ml, more than 40 μg/ml, more than 50 μg/ml, more than 60 μg/ml, more than 70 μg/ml, more than 80 μg/ml, more than 90 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ml, more than 130 μg/ml, more than 140 μg/ml, or more than 150 μg/ml. In some embodiments, the solubility of the water insoluble COX-2 inhibitors is measured at 4 hours. In some embodiments, the solubility of the water insoluble COX-2 inhibitors is measured at 24 hours. In some embodiments, the solubility of the water insoluble COX-2 inhibitors is measured at 48 hours.
- In some embodiments, the pharmaceutical compositions described herein include one or more viscosity modifiers. In some embodiments, the viscosity modifier is benzyl alcohol.
- Antioxidants
- In some embodiments, the pharmaceutical composition described herein also contains at least one antioxidant, which may increase the stability of the COX-2 inhibitor in solution. Examples of suitable antioxidants include, but are not limited to, citric acid monohydrate, histidine, monothioglycerol, niacinamide, phosphoric acid, potassium metabisulfite, sodium ascorbate, sodium bisulfate acetone, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, tartaric acid, or any derivative or combination thereof. Other examples of suitable antioxidants include, but are not limited to, cysteine hydrochloride monohydrate, thiolyglycolic acid, thiolacetic acid, dithiothreitol, reduced glutathione, thiourea, alpha-thioglycerol, cysteine, acetylcysteine, methionine, mercaptoethane, sulfonic acid, metabisulfite, ascorbic acid ascorbic acid derivatives (e.g., ascorbyl palmitate), sodium citrate, an organic compound having at least one thiol, an alkyl polyhydroxylated compound, a cycloalkyl polyhydroxylated compound, a hydroxypolycarboxylic acid, an alpha-hydroxy polycarboxylic acid (e.g., citric acid), tocotrienol, dimethyl glycine, betaine, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, polyethylene glycol, succinate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, dithiocarbamates or any combination thereof. In some embodiments, the pharmaceutical composition is free of polyethylene glycol or a derivative thereof. In other embodiments, the pharmaceutical composition is free of sulfites. In some embodiments, the antioxidant is cysteine hydrochloride monohydrate. In some embodiments, the antioxidant is mannitol.
- In some embodiments, the antioxidant is any antioxidant that can be used with the pharmaceutical compositions described herein. In some embodiments, the antioxidant is in a solution form before it is incorporated into a pharmaceutical composition. In some embodiments, the antioxidant solution includes ethanol. In some embodiments, the antioxidant solution may be the same as a solubilizing agent, such as ethanol. In some embodiments, the antioxidant helps prevent formation of an oxidation product of rofecoxib, including 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione, 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone, and/or dicarboxylate derivative of rofecoxib. In some embodiments, the antioxidant reduces the formation of 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione, 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone, and/or dicarboxylate derivative of rofecoxib by 5%, 10%, 15%, 20%, 25%, 50%, or 75% or more.
- In some embodiments, the amount % (w/w) of the antioxidant in a solid or lyophilized formulation of the water insoluble COX-2 inhibitor prior to reconstitution is about 0.01% (w/w) to about 5.0% (w/w). In some embodiments, the amount % (w/w) of the antioxidant is about 0.01% (w/w), 0.05% (w/w), 0.10% (w/w), 0.15% (w/w), about 0.17% (w/w), about 0.20% (w/w), about 0.30% (w/w), about 0.40% (w/w), about 0.45% (w/w), about 0.50% (w/w), about 0.52% (w/w), about 0.55% (w/w), about 0.60% (w/w), about 0.70% (w/w), about 0.80% (w/w), about 1.0% (w/w), about 1.3% (w/w), about 1.5% (w/w), about 1.7% (w/w), about 2.0% (w/w), about 2.2% (w/w), about 2.3% (w/w), about 2.5% (w/w), about 2.7% (w/w), about 2.8% (w/w), about 3.0% (w/w), about 3.2% (w/w), about 3.5% (w/w), about 3.6% (w/w), about 4.0% (w/w), about 4.7% (w/w), or any other suitable amount of antioxidant % (w/w) from about 0.10% (w/w) to about 5.0% (w/w). In some embodiments, the amount % (w/w) of antioxidant is about 0.30% (w/w) to about 1.0% (w/w). In some embodiments, the amount % (w/w) of antioxidant is about 0.50% (w/w).
- In some embodiments, the concentration of the antioxidant in an aqueous formulation of a water insoluble COX-2 inhibitor prior to administration ranges from about 0.01 mg/ml to about 10 mg/ml. In some embodiments, the concentration of the antioxidant is about 0.02 mg/ml, about 0.03 mg/ml, about 0.05 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.10 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.15 mg/ml, about 0.18 mg/ml, about 0.20 mg/ml, about 0.22 mg/ml, about 0.25 mg/ml, about 0.27 mg/ml, about 0.30 mg/ml, about 0.40 mg/ml, about 0.45 mg/ml, about 0.50 mg/ml, about 0.60 mg/ml, about 0.80 mg/ml, about 1.2 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 5.0 mg/ml, about 6.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 9 mg/ml, about 9.5 mg/ml, or any other suitable concentration of antioxidant from about 0.01 mg/ml to about 10 mg/ml. In some embodiments, the concentration of the antioxidant is about 0.08 mg/ml to about 0.50 mg/ml. In some embodiments, the concentration of the antioxidant is about 0.25 mg/ml.
- Buffering Agents
- In some embodiments, an aqueous formulation of a COX-2 inhibitor contains at least one buffering agent, which may maintain the pH of the formulation within an acceptable range as described herein. In some embodiments, the buffer used is a buffer compatible with parenteral administration in a subject, the pH of which may be adjusted between about 2 and about 8. In some embodiments, the pH of an aqueous formulation of a COX-2 inhibitor is from about pH 2 to about
pH 8, pH 3 to aboutpH 8, orpH 4 to aboutpH 8. In some embodiments, the pH is about pH 4.5, about pH 4.6, about pH 4.8, about pH 5.0, about pH 5.5, about pH 6.2, about pH 6.5, about pH 7.5, or any other suitable pH value from about pH4 to aboutpH 8. In some embodiments, the pH of the aqueous formulation is from aboutpH 5 to about pH 7.0. In some embodiments, the pH is about pH 5.2, about pH 5.5, about pH 5.6, about pH 6.0, about pH 6.4, or any other suitable pH value from aboutpH 5 to about pH 7.0. In some embodiments, the aqueous formulation of a COX-2 inhibitor has a pH of about 5 to about 6. - In some embodiments, an aqueous formulation of a COX-2 inhibitor contains at least one buffering agent with a pKa from about 4.5 to about 6.5. In some embodiments, the pKa is about 4.6, about 4.8, about 5.0, about 5.2, about 5.3, about 5.4, about 5.5, about 5.8, about 6.0, about 6.2, about 6.4, or any other suitable pKa from about 4.5 to about 6.5.
- In some embodiments, the buffering agent is a pharmaceutically acceptable salt or acid of citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, histidine or other amino acids, gluconate, malate, tryptophan, succinate, formate, propionate, carbonate, or any combination thereof adjusted to an appropriate pH, as described herein, with acid (for example, hydrochloric acid) or base (for example, sodium hydroxide).
- In some embodiments, the amount % (w/w) of the buffering agent in the solid or lyophilized formulation of the COX-2 inhibitor prior to reconstitution is about 0.05% (w/w) to about 2% (w/w). In some embodiment, the amount % (w/w) of the buffering agent lyophilized form is about 0.08% (w/w), about 0.10% (w/w), about 0.15% (w/w), about 1.0% (w/w), about 1.3% (w/w), about 1.5% (w/w), about 1.7% (w/w), about 0.20% (w/w), about 0.22% (w/w), about 0.25% (w/w), about 0.26% (w/w), about 0.27% (w/w), about 0.28% (w/w), about 0.30% (w/w), about 0.35% (w/w), about 0.40% (w/w), about 0.50% (w/w), about 0.60% (w/w), about 0.70% (w/w), about 0.80% (w/w), about 1.2% (w/w), about 1.4% (w/w), about 1.5% (w/w), about 1.7%, or any other suitable amount of buffering agent % (w/w) from about 0.05% (w/w) to about 2.0% (w/w). In some embodiments, the amount % (w/w) of the buffering agent is about 0.10% to about 0.70%. In some embodiments, the amount % (w/w) of the buffering agent is about 0.26%.
- In some embodiments, the concentration of the buffering agent in an aqueous formulation of a COX-2 inhibitor prior to administration ranges from about 0.01 mg/ml to about 10 mg/ml. In some embodiments the concertation is about 0.02 mg/ml, about 0.03 mg/ml, about 0.05 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.10 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.15 mg/ml, about 0.30 mg/ml, about 0.5 mg/ml, about 0.8 mg/ml, about 1.2 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 5.0 mg/ml, about 6.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 9 mg/ml, about 9.5 mg/ml, or any other suitable concentration of buffering agent from about 0.01 mg/ml to about 10 mg/ml. In some embodiments, the concentration of buffering agent is about 0.08 mg/ml to about 0.30 mg/ml. In some embodiments, the concentration of buffering agent is about 0.13 mg/ml.
- In some embodiments, the buffering agent helps prevent formation of an oxidation product of rofecoxib, including 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione and/or 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments, the buffering agent reduces the formation of 4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione and/or 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone by 25%, 50%, or 75% or more.
- Isotonicity Agents
- In some embodiments, an aqueous formulation of a COX-2 inhibitor also contains one or more isotonicity agents, which may maintain the osmolality of the formulation in a range that is physiologically compatible. In some embodiments, the osmolality of the formulation is physiologically compatible with an intravenous administration of the inhibitor. In some embodiments, the osmolality of the formulation is about 230 mOsm/L to about 420 mOsm/L. In some embodiments, the osmolality is about 240 mOsm/L, about 250 mOsm/L, about 260 mOsm/L, about 270 mOsm/L, about 276 mOsm/L, about 290 mOsm/L, about 300 mOsm/L, about 305 mOsm/L, about 310 mOsm/L, about 320 mOsm/L, about 350 mOsm/L, about 375 mOsm/L, about 400 mOsm/L or any other suitable osmolality from about 240 mOsm/L to about 420 mOsm/L. In some embodiments, the osmolality of the aqueous formulation is about 276 mOsm/L to about 320 mOsm/L. In some embodiments, the osmolality of the formulation is about 290 mOsm/L, about 295 mOsm/L, about 300 mOsm/L, about 305 mOsm/L, about 310 mOsm/L, about 315 mOsm/L, or any other suitable osmolality from about 276 mOsm/L to about 320 mOsm/L. In one embodiment, the osmolality of the aqueous formulation is about 200 mOsm/L-400 mOsm/L. Suitable agents for adjusting the isotonicity of the aqueous formulations of COX-2 inhibitors include, but are not limited to, mannitol, sorbitol, glycerol, sucrose, glucose, dextrose, levulose, fructose, lactose, polyethylene glycols 400 to 4000, phosphates, sodium chloride, potassium chloride, calcium chloride, calcium glucono-glucoheptonate, dimethyl sulfone. In some embodiments, the isotonicity agent is mannitol. In some embodiments, the isotonic agent is sodium chloride.
- In some embodiments, the amount % (w/w) of the isotonicity agent in the solid or lyophilized form of the COX-2 inhibitor formulation prior to reconstitution is about 5% (w/w) to about 95% (w/w). In some embodiments, the amount % (w/w) of the isotonicity agent is about 10% (w/w), about 15% (w/w), about 20% (w/w), about 25% (w/w), about 30% (w/w), about 35% (w/w), about 40% (w/w), about 45% (w/w), about 50% (w/w), about 55% (w/w), about 60% (w/w), about 65% (w/w), about 70% (w/w), about 72% (w/w), about 74% (w/w), about 76% (w/w), about 78% (w/w), about 79% (w/w), about 80% (w/w), about 81% (w/w), about 82% (w/w), about 84% (w/w), about 86% (w/w), about 90% (w/w), about 92% (w/w), or any other suitable amount of isotonicity agent % (w/w) from about 5% (w/w) to about 95% (w/w). In some embodiments, the amount of isotonicity agent % (w/w) is about 65% (w/w) to about 85% (w/w). In some embodiments, the amount of isotonicity agent % (w/w) is about 79%.
- In some embodiments, the concentration of the isotonicity agent in an aqueous formulation of a COX-2 inhibitor prior to administration ranges from about 1.0 mg/ml to about 150 mg/ml. In some embodiments, the concentration of the isotonicity agent is about 1.0 mg/ml, about 2.0 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 4.5 mg/ml, about 5.0 mg/ml, about 8.0 mg/ml, about 12 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 32 mg/ml, about 35 mg/ml, about 37 mg/ml, about 38 mg/ml, about 40 mg/ml, about 50 mg/ml, about 60 mg/ml, about 75 mg/ml, about 80 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 140 mg/ml, or any other suitable concentration of isotonicity agent from about 5 mg/ml to about 150 mg/ml.
- In some embodiments, the aqueous formulation does not include one or more of the following excipients: ethyl alcohol, glycerin, glyceryl monocaprylate, L-menthol, lauroyl polyoxyl-32 glycerides, medium chain triglycerides, monoammonium glycyrrhizinate, peppermint flavor,
polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, propyl gallate, or sucralose. - Combination Therapies
- The pharmaceutical compositions described herein can also be administered in combination with other therapeutic reagents. In some embodiments, such additional therapeutic agents include, but are not limited to, analgesics, antipyretics, or anti-inflammatory agents. In some embodiments, where a combination therapy is employed, other agents do not have to be administered in the same pharmaceutical composition as the COX-2 inhibitor, and may, because of different physical and chemical characteristics, be administered by different routes.
- In some embodiments, the therapeutic agent may be administered concurrently (for example, simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the severity of pain experienced by the patient, the nature of the disease, disorder, or condition, the condition, and the actual choice of compounds used. For combination therapies described herein, dosages of the compounds to be co-administered with an aqueous formulation of the COX-2 inhibitor will vary depending on the type of co-drug employed, on the amount of pain experienced by the patient, the risk for addiction, the disease or condition being treated among other factors. In addition, when co-administered with one or more biologically active agents, the aqueous formulation of a COX-2 inhibitor provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially.
- The multiple therapeutic agents (one of which is the aqueous formulation of a COX-2 inhibitor as described herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified intravenous form, or in multiple forms (by way of example only, either as a single intravenous formulation, as multiple intravenous formulations, or as intravenous formulation and a pill). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than 1 minute to less than 12 hours. In some embodiments, the timing between the multiple doses is from between about 1 minute to about 6 hours, or about 1 minute and about 3 hours, or about 1 minute and about 1 hour. In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations is also envisioned.
- The pharmaceutical agents which make up the combination therapy disclosed herein may be a combined dosage form (i.e., a combined IV formulation) or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent.
- The compounds described herein and combination therapies can be administered before, during or after the occurrence of a fever or painful condition, and the timing of administering the composition containing a compound can vary. Thus, for example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop conditions (e.g., body aches and chills following chemotherapy treatment) or diseases in order to prevent the occurrence of the disease or condition. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, preferably within the first 48 hours of the onset of the symptoms, more preferably within the first 6 hours of the onset of the symptoms, and most preferably within 3 hours of the onset of the symptoms.
- Formulations
- Pharmaceutical Composition for Intravenous Administration:
- In some embodiments, intravenous formulations of the pharmaceutical compositions described herein are in the form of a powder to be reconstituted in solution under sterile conditions prior to administration. In some embodiments, the powder is a lyophilization product of a solution described herein. In other embodiments, the intravenous formulations are provided as sterile solutions ready for administration. In other embodiments, the intravenous formulations are in a concentrated form and ready for administration following dilution with a solution. Appropriate containers for storage and transport of the pharmaceutical compositions described herein include, but are not limited to, vials, bags, bottles, ampules, or any suitable containers for intravenous formulations known in the art.
- “Ready to Use” Pharmaceutical Composition
- In some embodiments, the pharmaceutical compositions disclosed herein can be prepared and administered in dose units. Liquid dose units are vials or ampoules for injection or other parenteral administration. In some embodiments, the vial or ampule contains 50 ml, 60 ml, 70 ml, 80, ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml of a COX-2 inhibitor solution. In some embodiments the vial or ampule contains 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg or more of a water insoluble COX-2 inhibitor.
- “Concentrate” Pharmaceutical Composition
- In some embodiments, the pharmaceutical composition described herein is diluted with a water-based solution to create an infusate that is ready for administration. Several types of concentrated compositions can be used. The concentrate can contain 50 μg/ml, 100 μg/ml, 150 μg/ml, 200 μg/ml, 250 μg/ml, 300 μg/ml, 350 μg/ml, 400 μg/ml, 450 μg/ml, 500 μg/ml or more of the water insoluble COX-2 inhibitor. In one embodiment, a bag, vial, bottle, or other container is partially filled with the concentrated pharmaceutical composition and a pharmacist or healthcare provide adds 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, 200 ml or more of a diluent to the container prior to intravenous administration. In another embodiment, a bag, vial, bottle, or other container with the concentrated pharmaceutical composition is provided and a pharmacist or healthcare provider removes 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, or 200 ml of the concentrate and adds it to 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 170 ml, 180 ml, 190 ml, 200 ml or more of a diluent to create the infusate. In yet another embodiment, an empty bag, vial, bottle, or other container is provided and a pharmacist or healthcare provider adds 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml or more of diluent and 5 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml or more of concentrate to create an infusate. In some embodiments, the infusate comprises 15 ml, 20 ml, 25 ml, 30 ml, 35 ml, 40 ml, 45 ml, 50 ml, 55 ml, 60 ml, 65 ml, 70 ml, 75 ml, 80 ml, 85 ml, 90 ml, 95 ml, 100 ml or more of the concentrate and diluent.
- “Lyophilized” Pharmaceutical Composition
- In some embodiments, the pharmaceutical composition described herein may be a lyophilized pharmaceutical composition comprising a lyophilization product of the aqueous formulations described herein. The lyophilization product may comprise 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg or more of a water insoluble COX-2 inhibitor. The lyophilization product may be reconstituted in solution under sterile conditions prior to administration.
- In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is an oral suspension. In some embodiments, the pharmaceutical composition is an oral solution. In some embodiments, the pharmaceutical composition is a solution suitable for injection.
- Pharmaceutical Composition for Oral Administration:
- In some embodiments, the oral solution may further contain at least one flavoring agent or taste masking agent. Non-limiting exemplary list of flavoring agents/taste masking agents: natural and synthetic flavoring liquids such as volatile oils, synthetic flavor oils, flavoring aromatic oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. Non-limiting representative examples of volatile oils include spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, menthol, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice oil, oil of sage, mace extract, oil of bitter almond, and cassia oil. Also artificial, natural or synthetic flavors including fruit flavors such as vanilla, and citrus oils including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, banana and other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral, i.e., alphocitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin), bubble gum flavor, mixtures thereof and the like.
- In some embodiments, the oral solution may further contain a sweetener. Non-limiting exemplary list of sweeteners: sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof, saccharin and its various salts such as the sodium or calcium salt; cyclamic acid and its various salts such as the sodium salt; the dipeptide sweeteners such as aspartame, acesulfame K, and other sweeteners like magnasweet, sucralose, mixtures thereof and the like.
- Methods
- In some embodiments, the subject matter disclosed herein provides a method of treating pain, fever, or inflammation in a subject in need thereof, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject. In some embodiments, the subject matter disclosed herein provides a method of managing mild to moderate pain in a subject, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject. In some embodiments, the subject matter disclosed herein provides a method of managing moderate to severe pain, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject with adjunctive opioid analgesics. In some embodiments, the subject matter disclosed herein provides a method of reducing fever in a subject, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject. In some embodiments, the subject matter disclosed herein provides a method of short-term (<5 days) management of moderately severe acute pain, which requires analgesia at the opioid level in a subject, wherein a pharmaceutical composition including a water insoluble COX-2 inhibitor is administered to the subject.
- The aqueous formulations of the water insoluble COX-2 inhibitors described herein can be used for reducing pain conditions including, but not limited to, acute nociceptive pain, acute neuropathic pain, postoperative pain, lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, opioid-resistant pain, visceral pain, surgical pain, procedural pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post-partum pain, headache, muscular aches, backache, arthritis pain, the common cold, toothache, dental pain, osteoarthritis pain, menstrual pain, menstrual cramps, migraine, and genitourinary tract-related pain including cystitis. In some embodiments, the aqueous formulation is administered prior to the onset of pain or a pain inducing condition or stimulus, for example prior to a surgical operation. In some embodiments, the aqueous formulations of water insoluble COX-2 inhibitors described herein are used to reduce fever, including, but not limited to, fever due to infections, drug reactions, allergic reactions, transfusion reactions, stroke, surgery, heat stroke, rheumatic diseases, cancer, or fever of unknown origin. In some embodiments, the aqueous formulations described herein are administered to a patient undergoing a dental procedure.
- Dosages and Dosing Regimens
- In some embodiments a single dose formulation of a water insoluble COX-2 inhibitor contains 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
- In some embodiments, the concentration of a water insoluble COX-2 inhibitor in an aqueous formulation is about 0.001% (w/v) to about 0.07% (w/v). In some embodiments, the concentration (w/v) of a COX-2 inhibitor in an aqueous formulation is about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% or any other suitable concentration. In one embodiment, the concentration of the COX-2 inhibitor is from about 0.01% to about 0.03% (w/v).
- Depending on the concentration of the water insoluble COX-2 inhibitor in the aqueous formulation and consistent with the suitable dose levels described herein, the volume of aqueous formulation administered can vary from about 1 ml to about 200 ml. In some embodiments, the volume of an aqueous formulation is about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 10 ml, 20 ml, 25 mL, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80, ml, 90 ml, 100 ml, 110 ml, 120 ml, 130 ml, 140 ml, 150 ml, 160 ml, 180 ml, or any suitable volume of the aqueous formulation. In some embodiments, the volume of the aqueous formulation is about 75 ml to about 125 ml. In another embodiment, the volume is about 40 ml to about 75 ml. In yet another embodiment, the volume of the aqueous formulation is about 100 ml.
- In some embodiments, the dosing regimen of the pharmaceutical composition described herein is a once daily administration. In some embodiments, the dosing regimen of the pharmaceutical composition described herein is multiple times per day. In some embodiment, the dosing regimen of the pharmaceutical composition described herein is twice per day, three times per day, four times per day, five times per day, or six times per day. In some embodiments, the dosing regimen is three times per day of intravenous administration of the pharmaceutical composition. In some embodiments, the dosing regimen is four times per day of intravenous administration of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 5 mg to 15 mg of rofecoxib and is administered in a 100 ml infusate three to four times per day.
- An aqueous formulation of a water insoluble COX-2 inhibitor can be administered in an interval to allow for the administration of about 10 mg to about 200 mg in a 24 hour period. In some embodiments, the aqueous formulation is administered in an interval sufficient to allow for the administration of about 20 mg to 100 mg in a 24 hour period. In some embodiments, the aqueous formulation is administered between 1 to 6 times every twenty-four hours. In some embodiments, the frequency of administration is not greater than once every four hours.
- In various embodiments, the aqueous formulation of a water insoluble COX-2 inhibitor is dosed so as to provide less than about 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg over a 24-hour period. In various embodiments, the aqueous formulation is dosed three to six times in a 24-hour period. For example, in some embodiments, the aqueous formulation is dosed three times in a 24-hour period. In other embodiments, the aqueous formulation is dosed four times in a 24-hour period. In still other embodiments, the aqueous formulation is dosed five times in a 24-hour period. In some embodiments, the aqueous formulation is dosed six times in a 24-hour period. In some embodiments, the aqueous formulation is dosed seven times in a 24-hour period. In some embodiments, the aqueous formulation is dosed eight times in a 24-hour period.
- In some embodiments, the infusion time of the intravenous formulation of the COX-2 inhibitor is about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 45 min, about 50 min, about 60 min or more. In some embodiments, the infusion time is between 10 min and 30 min. In some embodiments, the infusion time ranges from about 1 minute to about 1 hour. In some embodiments, the infusion time is about 5 minutes, about 10 minutes, about 11 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, or any other suitable administration time from about 1 minute to about 1 hour. In some embodiments, the amount of time required for administration of the intravenous formulation ranges from about 5 minutes to about 45 minutes, or about 5 minutes to about 30 minutes, or about 5 minutes to about 15 minutes.
- In some embodiments, the aqueous formulation of a COX-2 inhibitor is administered to a subject within about 12 hours after a surgical intervention, within 11 hours, 10 hours, 9 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hours, 45 minutes, 30
minutes 15 minutes, 5 minutes, or any period within about 12 hours following a surgical intervention. In some embodiments, a subject is administered the aqueous formulation prior to a surgical intervention, about 4 hours or less prior to the surgical intervention, about 3 hours, 2 hours, 1 hours, 30 minutes, 15 minutes or during the surgical intervention itself. - In some embodiments, the compositions described herein include the COX-2 inhibitor rofecoxib (also known as TRM-201) in a solution comprising hydroxypropyl β-cyclodextrin (HPbCD) or sulfobutyl ether-β-cyclodextrin (e.g., Captisol®) and water as shown in
FIGS. 1 and 3 and Table 1 below: -
TABLE 1 Vehicle Compositions. TRM-201 solubility Vehicle # Vehicle Composition (μg/mL) @ t = 24 h V138 (V8) 20/80 (w/v) HPbCD / Water 123 V169 30/70 (w/v) HPbCD / Water 207 V170 40/60 (w/v) HPbCD / Water 306 V171 50/50 (w/v) HPbCD / Water 400 V172 60/40 (w/v) HPbCD / Water 527 V174 20/80 (w/v) Captisol ® / Water 113 V175 30/70 (w/v) Captisol ® / Water 183 V176 40/60 (w/v) Captisol ® / Water 241 V177 50/50 (w/v) Captisol ® / Water 314 V178 60/40 (w/v) Captisol ® / Water 349 - By comparison, the prior art, U.S. Pat. No. 6,063,811, teaches an intravenous formulation of rofecoxib comprising only 1 mg of rofecoxib per 200 mL of solution.
- In some embodiments, the vehicle composition includes a cyclodextrin and water in a 15/85 (w/v) ratio. In some embodiments, addition of a second solubilizing agent to the vehicle composition increases solubility of the water insoluble COX-2 inhibitor. In some embodiments, addition of a second solubilizing agent increases the solubility of the water insoluble COX-2 inhibitor to 110 μg/ml, 115 μg/ml, 120 μg/ml, 130 μg/ml, 140 μg/ml or greater.
- In some embodiments, the second solubilizing agent is a co-solvent helper such as ethanol,
PS 20, orPS 80. In some embodiments, the second solubilizing agent is Soluplus®. In some embodiments, addition of the second solubilizing agent increases the solubility of the water insoluble COX-2 inhibitor to 120 μg/ml or greater. - A study was performed to assess the solubility of rofecoxib in a composition comprising water, a cyclodextrin, and a second solubilizing agent. 20 mg of TRM-201 (rofecoxib) was mixed with 1.2 ml of each vehicle solution in a 2-ml microcentrifuge tube and tumbled at ambient conditions. At t=24 h, 300 μL of each mixture was drawn and filtered through 0.2 m, Nylon membrane by centrifugation (14000 rpm, 5 min). Each filtrate was diluted 10-fold with diluent (10/90 (v/v) ACN/MeOH) for UPLC assay. The vehicle compositions and results are shown in
FIG. 2 and Table 2 below: -
TABLE 2 Vehicle Compositions. TRM-201 solubility Vehicle # Vehicle Composition (μg/mL) @ t = 24 h V204 5/15/80 (v/w/v) DMSO / HPbCD / Water 75.5 V205 5/15/80 (v/w/v) EtOH / HPbCD / Water 79.9 V206 5/15/80 (w/w/v) Kolliphor HS 15 / HPbCD / Water 83.1 V207 5/15/80 (w/w/v) Poloxamer 188 / HPbCD / Water 92.8 V208 5/15/80 (v/w/v) PS 20 / HPbCO / Water 88.5 V209 5/15/80 (v/w/v) PS 80 / HPbCO / Water 100 V210 5/15/80 (w/w/v) Soluplus / HPbCD / Water 111.2 V211 5/5/15/75 (w/w/w/v) Soybean oil/ Span 40 / HPbCD / Water 115.8 V212 5/15/80 (v/w/v) DMSO / Captisol / Water 95.2 V213 5/15/80 (v/w/v) EtOH / Captisol / Water 78.9 V214 5/15/80 (w/w/v) Kolliphor HS 15 / Captisol / Water 113.7 V215 5/15/80 (w/w/v) Poloxamer 188 / Captisol / Water 99.1 V216 5/15/80 (v/w/v) PS 20/ Captisol / Water 85.1 V217 5/15/80 (v/w/v) PS 80 / Captisol / Water 137 V218 5/15/80 (w/w/v) Soluplus / Captisol / Water 140.5 V219 5/5/15/75 (w/w/w/v) Soybean oil/ Span 40 / Captisol / Water 135.3 - This study demonstrates that, in certain circumstances, addition of a second solubilizing agent can increase the solubility of rofecoxib in an water-based solution. Surprisingly, the addition of a second solubilizing agent differentially affected the solubility of rofecoxib in hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin. For example, a 5/15/80 (w/w/v) mixture of Soluplus®/Captisol/Water (V218) achieved a solubility of rofecoxib of 140.5 μg/ml at t=24 h, whereas a 20/80 (w/v) mixture of Captisol/Water (V174) achieved a solubility of rofecoxib of 113 μg/ml at t=24 h. In some embodiments, addition of a second solubilizing agent to the pharmaceutical composition increases the solubility of a water insoluble COX-2 inhibitor by 5%, 10%, 15%, 20%, 25%, 30% or more. In contrast, a 5/15/80 (w/w/v) mixture of Soluplus®/hydroxypropyl-β-cyclodextrin/Water (V204) achieved a solubility of rofecoxib of 111.2 μg/ml at t=24 h, whereas a 20/80 (w/v) mixture of hydroxypropyl-β-cyclodextrin/Water (V138) achieved a solubility of rofecoxib of 123 μg/ml at t=24 h.
- In some embodiments, the pharmaceutical composition described herein includes about 10 μg/ml of rofecoxib. In some embodiments, the pharmaceutical composition further includes at least one β-cyclodextrin and water. In some embodiments, the pharmaceutical composition is 10 μg/ml of rofecoxib in β-cyclodextrin and water.
- In some embodiments, the pharmaceutical composition is in a 100 ml “ready to use” form. In some embodiments, the pharmaceutical composition is concentrated and has to be diluted to a 100 ml volume prior to use to create the infusate. In some embodiments, the 100 ml infusate is intravenously administered to a subject 3-4 times per day to treat acute pain in a surgical setting, for example to treat post-operative pain.
- A study was performed to assess the solubility of rofecoxib in a number of different compositions comprising a solubilizing agent, a co-solvent helper, and/or other excipients. In some embodiments, the compositions (e.g. oral solution or composition for intravenous administration) described herein may comprise any of the following compositions or components as described in
FIGS. 1 and 3 and Table 3 below. -
TABLE 3 Vehicle Compositions. TRM-201 solubility Vehicle # Vehicle Composition (μg/mL) @ t = 24 h V01 2/98 (v/v) BnOH / Water 9 V02 10/90 (v/v) Corn oil / Water 18 V03 40/60 (v/v) Kolliphor EL/ 294 Water V04 50/50 (v/v) Kolliphor EL / 2055 EtOH V05 10/90 (v/v) DMSO / Water 8 V06 30/70 (v/v) DMA / Water 63 V07 1/99 (v/v) Glyceryl 8 monooleate / Water V08 20% (w/v)HPbCD in water 110 V09 1% (w/v) Lecithin in water 10 V10 20/80 (v/v) NMP / Water 40 V11 20/80 (v/v) Miglyol 812 N / 11 Water V12 1% (w/v) Oleic acid in water 33 V13 10% (w/v) Poloxamer 188 in 10 water V14 40/60 (v/v) Water / PEG 400 461 V15 10/90 (v/v) PS 20 / Water 68 V16 40/60 (v/v) PS 80 / Water 367 V17 10% (w/v) Povidone K30 in 9 water V18 30/70 (v/v) Propylene glycol / 16 Water V19 10/90 (v/v) Sorbitol / Water 6 V20 10% (w/v) Vitamin E TPGS 157 in water V21 100% Water 6 V22 100% Ethanol 317 V23 50/50 (v/v) PS 80 / EtOH 2287 V24 50/50 (v/v) PEG 400 / EtOH 3996 V25 40% (w/v) Vitamin E TPGS 2109 in EtOH V26 20/40/40 (v/v/v) EtOH / 5804 Kolliphor EL / PEG 400 V27 20/40/40 (v/v/v) NMP / 19408 Kolliphor EL / PEG 400 V28 20/40/40 (v/v/v) EtOH / 3881 Kolliphor EL / PS 80 V29 20/40/40 (v/v/v) EtOH / PS 6171 80 / PEG 400 V30 20/40/40 (v/w/v) EtOH / 6973 Vitamin E TPGS / PEG 400 V31 10/40/50 (v/v/v) BnOH / 4775 EtOH / PEG 400 V32 10/40/50 (v/v/w) BnOH / 545 EtOH / Decanoic acid V33 40% (w/v) Kolliphor HS 15 1819 in EtOH V34 20/40/40 (v/w/v) EtOH / 6295 Kolliphor HS 15 / PEG 400 V35 10% (w/v) Poloxamer 188 in 817 EtOH V36 100% Soybean oil 293 V37 10% (w/v) Span 40, 10% 284 (w/v) Cholesterol in water V38 40% (w/v) Soluplus in EtOH 1533 V39 50/50 (v/v) Glycerin / EtOH 489 V40 1% (w/v) Albumin in PBS 3 (1X) V41 50/50 (v/v) Transcutol / 2215 EtOH V42 40/60 (v/v) EtOH / Isopropyl 258 myristate 10/18/36/36 (v/v/v/v) Water / 8357 NMP / Kolliphor EL / PEG 400 V43 10/10/80 (v/v/v) PS 80 / PEG 112 400 / Water V44 10/10/80 (v/v/v) PS 80 / PEG 115 300 / Water V45 10/10/80 (v/v/v) Kolliphor 96 EL / PEG 400 / Water V46 10/10/10/70 (v/v/v/v) EtOH / 124 PS 80 / PEG 400 / Water V47 10/10/10/70 (v/v/v/v) NMP / 160 PS 80 / PEG 400 / Water V48 10/10/10/70 (v/v/v/v) DMA / 150 PS 80 / PEG 400 / Water V49 10/10/10/70 (v/v/v/v) 122 Glycerin / PS 80 / PEG 400 / Water V50 10/10/10/70 (v/v/v/v) PG/PS 124 80 / PEG 400 / Water V51 20/20/60 (v/v/v) PS 80 / PEG 246 400 / Water V52 20/20/60 (v/v/v) PS 80 / PEG 228 300 / Water V53 V53, 10/20/20/50 (v/v/v/v) 319 EtOH / PS 80 / PEG 400 / Water V54 10/20/20/50 (v/v/v/v) NMP / 409 PS 80 / PEG 400 / Water V55 10/20/20/50 (v/v/v/v) DMA / 387 PS 80 / PEG 400 / Water V56 10/20/20/50 (v/v/v/v) 288 Glycerin / PS 80 / PEG 400 / Water V57 10/20/20/50 (v/v/v/v) PG / PS 301 80 / PEG 400 / Water V58 40/10/50 (v/v/v) PS 80 / PEG 499 400 / Water V59 25/25/50 (v/v/v) PS 80 / PEG 390 400 / Water V60 10/40/50 (v/v/v) PS 80 / PEG 276 400 / Water V61 60/20/20 (v/v/v) PS 80 / PEG 2220 400 / Water V62 20/60/20 (v/v/v) PS 80 / PEG 2856 400 / Water V63 10/60/30 (v/v/v) PS 80 / PEG 1157 400 / Water V64 5/1/64/30 (v/v/v/v) EtOH / PS 1137 80 / PEG 400 / Water V65 5/65/30 (v/v/v) PS 80 / PEG 1177 400 / Water V66 1/69/30 (v/v/v) PS 80 / PEG 1180 400 / Water V67 70/30 (v/v) PEG 400 / Water 1151 V68 10/50/40 (v/v/v) PS 80 / PEG 501 400 / Water V69 5/1/54/40 (v/v/v/v) EtOH / PS 451 80 / PEG 400 / Water V70 5/55/40 (v/v/v) PS 80 / PEG 461 400 / Water V71 1/59/40 (v/v/v) PS 80 / PEG 438 400 / Water V72 (V14) 60/40 (v/v) PEG 400 / Water 412 V73 (V60) 10/40/50 (v/v/v) PS 80 / PEG 247 400 / Water V74 5/1/44/50 (v/v/v/v) EtOH / PS 188 80 / PEG 400 / Water V75 5/45/50 (v/v/v) PS 80 / PEG 211 400 / Water V76 5/45/50 (v/v/v) EtOH / PEG 181 400 / Water V77 1/49/50 (v/v/v) PS 80 / PEG 181 400 / Water V78 50/50 (v/v) PEG 400 / Water 170 V79 5/1/34/60 (v/v/v/v) EtOH / PS 100 80 / PEG 400 / Water V80 5/35/60 (v/v/v) EtOH / PEG 92 400 / Water V81 1/39/60 (v/v/v) PS 80 / PEG 97 400 / Water V82 40/60 (v/v) PEG 400 / Water 89 V83 55/45 (v/v) PEG 400 / Water 425 V84 62.5/37.5 (v/v) PEG 400 / 228 Water V85 100% PEG 400 9668 V86 50/40/10 (v/v/v) PEG 400 / 214 Water / Glycerin V87 30/70 (v/v) PEG 300 / Water 23 V88 5/30/65 (w/v/v) Captisol / 47 PEG 300 / Water V89 5/30/65 (v/v/v) DMA / PEG 40 300 / Water V90 5/30/65 (v/v/v) DMSO / PEG 35 300 / Water V91 5/30/65 (v/v/v) EtOH / PEG 35 300 / Water V92 5/30/65 (w/v/v) HPbCD / 49 PEG 300 / Water V93 5/30/65 (v/v/v) Kolliphor EL 65 / PEG 300 / Water V94 5/30/65 (w/v/v) Kolliphor HS 57 15 / PEG 300 / Water V95 5/30/65 (v/v/v) NMP / PEG 38 300 / Water V96 5/30/65 (v/v/v) PG / PEG 300 33 / Water V97 5/30/65 (v/v/v) PS 20 / PEG 67 300 / Water V98 5/30/65 (v/v/v) PS 80 / PEG 78 300 / Water V99 30/70 (v/v) PEG 400 / Water 25 V100 5/30/65 (w/v/v) Captisol / 48 PEG 400 / Water V101 5/30/65 (v/v/v) DMA / PEG 41 400 / Water V102 5/30/65 (v/v/v) DMSO / PEG 34 400 / Water V103 5/30/65 (v/v/v) EtOH / PEG 37 400 / Water V104 5/30/65 (w/v/v) HPbCD / 55 PEG 400 / Water V105 5/30/65 (v/v/v) Kolliphor EL 72 / PEG 400 / Water V106 5/30/65 (w/v/v) Kolliphor HS 68 15 / PEG 400 / Water V107 5/30/65 (v/v/v) NMP / PEG 46 400 / Water V108 5/30/65 (v/v/v) PG / PEG 400 33 / Water V109 5/30/65 (v/v/v) PS 20 / PEG 65 400 / Water V110 5/30/65 (v/v/v) PS 80 / PEG 81 400 / Water V111 20/80 (v/v) PEG 300 / Water 13 V112 5/20/75 (w/v/v) Captisol / 33 PEG 300 / Water V113 5/20/75 (v/v/v) DMA / PEG 23 300 / Water V114 5/20/75 (v/v/v) DMSO / PEG 18 300 / Water V115 5/20/75 (v/v/v) EtOH / PEG 18 300 / Water V116 5/20/75 (w/v/v) HPbCD / 39 PEG 300 / Water V117 5/20/75 (v/v/v) Kolliphor EL 48 / PEG 300 / Water V118 5/20/75 (w/v/v) Kolliphor HS 42 15 / PEG 300 / Water V119 5/20/75 (v/v/v) NMP / PEG 23 300 / Water V120 5/20/75 (v/v/v) PG / PEG 300 17 / Water V121 5/20/75 (v/v/v) PS 20 / PEG 53 300 / Water V122 5/20/75 (v/v/v) PS 80 / PEG 62 300 / Water V123 20/80 (v/v) PEG 400 / Water 12 V124 5/20/75 (w/v/v) Captisol / 39 PEG 400 / Water V125 5/20/75 (v/v/v) DMA / PEG 21 400 / Water V126 5/20/75 (v/v/v) DMSO / PEG 19 400 / Water V127 5/20/75 (v/v/v) EtOH / PEG 19 400 / Water V128 5/20/75 (w/v/v) HPbCD / 43 PEG 400 / Water V129 5/20/75 (v/v/v) Kolliphor EL 53 / PEG 400 / Water V130 5/20/75 (w/v/v) Kolliphor HS 44 15 / PEG 400 / Water V131 5/20/75 (v/v/v) NMP / PEG 25 400 / Water V132 5/20/75 (v/v/v) PG / PEG 400 17 / Water V133 5/20/75 (v/v/v) PS 20 / PEG 48 400 / Water V134 5/20/75 (v/v/v) PS 80 / PEG 63 400 / Water V135 10/90 (w/v) HPbCD / Water 57 V136 10/10/80 (w/v/v) HPbCD / 56 PEG 400 / Water V137 10/20/70 (w/v/v) HPbCD / 62 PEG 400 / Water V139 20/10/70 (w/v/v) HPbCD / 119 PEG 400 / Water V140 20/20/60 (w/v/v) HPbCD / 119 PEG 400 / Water V141(V104) 5/30/65 (w/v/v) HPbCD / 50 PEG 400 / Water V142 10/30/60 (w/v/v) HPbCD / 79 PEG 400 / Water V143 15/30/55 (w/v/v) HPbCD / 108 PEG 400 / Water V144 20/30/50 (w/v/v) HPbCD / 139 PEG 400 / Water V145 2/5/30/63 (v/w/v/v) EtOH / 52 HPbCD / PEG 400 / Water V146 2/10/30/58 (v/w/v/v) EtOH / 84 HPbCD / PEG 400 / Water V147 2/15/30/53 (v/w/v/v) EtOH / 102 HPbCD / PEG 400 / Water V148 2/20/30/48 (v/w/v/v) EtOH / 142 HPbCD / PEG 400 / Water V149 2/5/30/63 (w/w/v/v) 59 Kolliphor HS 15 / HPbCD / PEG 400 / Water V150 2/10/30/58 (w/w/v/v) 87 Kolliphor HS 15 / HPbCD / PEG 400 / Water V151 2/15/30/53 (w/w/v/v) 117 Kolliphor HS 15 / HPbCD / PEG 400 / Water V152 2/20/30/48 (w/w/v/v) 150 Kolliphor HS 15 / HPbCD / PEG 400 / Water V153 2/5/30/63 (v/w/v/v) PS 80/ 65 HPbCD / PEG 400 / Water V154 2/10/30/58 (v/w/v/v) PS 80 / 95 HPbCD / PEG 400 / Water V155 2/15/30/53 (v/w/v/v) PS 80/ 128 HPbCD / PEG 400 / Water V156 2/20/30/48 (v/w/v/v) PS 80 / 147 HPbCD / PEG 400 / Water V157 5/5/30/60 (v/w/v/v) EtOH / 65 HPbCD / PEG 400 / Water V158 5/10/30/55 (v/w/v/v) EtOH / 89 HPbCD / PEG 400 / Water V159 5/15/30/50 (v/w/v/v) EtOH / 122 HPbCD / PEG 400 / Water V160 5/20/30/45 (v/w/v/v) EtOH / 146 HPbCD / PEG 400 / Water V161 5/5/30/60 (w/w/v/v) 79 Kolliphor HS 15 / HPbCD / PEG 400 / Water V162 5/10/30/55 (w/w/v/v) 117 Kolliphor HS 15 / HPbCD / PEG 400 / Water V163 5/15/30/50 (w/w/v/v) 133 Kolliphor HS 15 / HPbCD / PEG 400 / Water V164 5/20/30/45 (w/w/v/v) 169 Kolliphor HS 15 / HPbCD / PEG 400 / Water V165 5/5/30/60 (v/w/v/v) PS 80 / 98 HPbCD / PEG 400 / Water V166 5/10/30/55 (v/w/v/v) PS 80 / 121 HPbCD / PEG 400 / Water V167 5/15/30/50 (v/w/v/v) PS 80 / 157 HPbCD / PEG 400 / Water V168 5/20/30/45 (v/w/v/v) PS 80 / 202 HPbCD / PEG 400 / Water V173 10/90 (w/v) Captisol / Water 55 V174.5 10/10/80 (w/v/v) Captisol / 56 PEG 400 / Water V180 10/20/70 (w/v/v) Captisol / 59 PEG 400 / Water V181 20/10/70 (w/v/v) Captisol / 102 PEG 400 / Water V182 20/20/60 (w/v/v) Captisol / 101 PEG 400 / Water V183 10/30/60 (w/v/v) Captisol / 68 PEG 400 / Water V184 15/30/55 (w/v/v) Captisol / 85 PEG 400 / Water V185 20/30/50 (w/v/v) Captisol / 104 PEG 400 / Water V186 2/10/30/58 (v/w/v/v) EtOH / 74 Captisol / PEG 400 / Water V187 2/15/30/53 (v/w/v/v) EtOH / 94 Captisol / PEG 400 / Water V188 2/20/30/48 (v/w/v/v) EtOH / 113 Captisol / PEG 400 / Water V189 2/10/30/58 (w/w/v/v) 77 Kolliphor HS 15 / Captisol / PEG 400 / Water V190 2/15/30/53 (w/w/v/v) 96 Kolliphor HS 15 / Captisol / PEG 400 / Water V191 2/20/30/48 (w/w/v/v) 123 Kolliphor HS 15 / Captisol / PEG 400 / Water V192 2/10/30/58 (v/w/v/v) PS 80 / 86 Captisol / PEG 400 / Water V193 2/15/30/53 (v/w/v/v) PS 80/ 108 Captisol / PEG 400 / Water V194 2/20/30/48 (v/w/v/v) PS 80 / 133 Captisol / PEG 400 / Water V195 5/10/30/55 (v/w/v/v) EtOH / 85 Captisol / PEG 400 / Water V196 5/15/30/50 (v/w/v/v) EtOH / 102 Captisol / PEG 400 / Water V197 5/20/30/45 (v/w/v/v) EtOH / 118 Captisol / PEG 400 / Water V198 5/10/30/55 (w/w/v/v) 116 Kolliphor HS 15 / Captisol / PEG 400 / Water V199 5/15/30/50 (w/w/v/v) 133 Kolliphor HS 15 / Captisol / PEG 400 / Water V200 5/20/30/45 (w/w/v/v) 149 Kolliphor HS 15 / Captisol / PEG 400 / Water V201 5/10/30/55 (v/w/v/v) PS 80 / 116 Captisol / PEG 400 / Water V202 5/15/30/50 (v/w/v/v) PS 80 / 138 Captisol / PEG 400 / Water V203 5/20/30/45 (v/w/v/v) PS 80 / 173 Captisol / PEG 400 / Water - In some embodiments, the subject matter disclosed herein relates to oral solution formulations of water insoluble COX-2 inhibitors. In some embodiments, the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib. In some embodiments, the water insoluble COX-2 inhibitor is rofecoxib. In some embodiments, the subject matter disclosed herein relates to oral solution formulations of rofecoxib.
- In some embodiments, the subject matter described herein relates to a single-dose, open-label, phase I, two-period crossover pharmacokinetic study of 17.5-mg doses of TRM-201 (rofecoxib) oral tablets and a solution of TRM-201 administered as an oral solution (TRM-201 OS) to healthy subjects in a fasting state.
- Study Objectives and Endpoint
- Primary Objectives:
- 1. To evaluate and compare key pharmacokinetic parameters of the
TRM 201 oral tablets andTRM 201 oral solution (TRM-201 OS). Key pharmacokinetic parameters include area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) and observed maximum plasma concentration (Cmax). - 2. To assess additional pharmacokinetic parameters of TRM-201 oral solution (OS) including time to observed maximum concentration (Tmax) and apparent terminal elimination half-life (t1/2).
- Secondary Objective:
- 3. To assess the safety and tolerability of TRM-201 OS and TRM-201 oral tablets administered to healthy subjects.
- Study Design:
- In some embodiments, the subject matter disclosed herein relates to a single-center, open-label, Phase I, two-period crossover pharmacokinetic (PK) study to assess single oral tablet and single oral solution administrations of TRM-201 in healthy subjects in a fasting state. Twelve heathy subjects who meet eligibility criteria will be randomized to receive one of two treatment sequences that consist of a single oral tablet of TRM-201 and a single oral solution of TRM-201 with the primary objectives of comparing the key PK parameters of the two dosage forms. Subjects will enter the clinic the day before their planned dosing and will remain in the clinic throughout the two-period crossover.
- The maximum duration for each subject's participation in the study is up 35 days: up to 27 days for screening (minus admission day) and 8 in-clinic days. The 8 in-clinic days consist of 1 day for check-in and 3 days for each of the two periods plus an additional washout day between Periods 1 and 2.
- Study Drug, Dosage and Route of Administration
- TRM-201: An immediate-release tablet that contains rofecoxib. An oral dose of 17.5 mg rofecoxib will be administered in the two-period crossover.
- TRM-201 OS (0.1 mg/mL Rofecoxib Oral Solution): An oral solution consisting of 0.1 mg/mL rofecoxib in 20% Captisol® in 50 mM citrate buffer pH 4.5 at a total dose administration of 17.5 mg of rofecoxib in 175 mL will be administered in the two-period crossover. The total amount of Captisol® to be consumed in the 175 mL oral solution is 35 g.
- Patient population: healthy subjects
- Number of subjects: 12
- Number of Centers: 1
- Test Product and Doses: TRM-201 Oral tablet, 17.5 mg and TRM-201 OS in 20% Captisol®, 17.5 mg in 175 mL
- Route of administration: oral
- Criteria for Inclusion/Exclusion:
- Inclusions: Subjects may be included in the study only if all the following criteria are met:
- 1. The subject is 18 to 60 years of age, inclusive, at Screening.
- 2. All female subjects must have a negative pregnancy test at Screening and Check-in. Female subjects of childbearing potential must be using an acceptable method of birth control during the study (i.e., diaphragm with spermicide, intrauterine device, condom with foam or vaginal spermicide, oral contraceptives, or abstinence). Women who are surgically sterile (i.e., hysterectomy, bilateral tubal ligation, bilateral salpingectomy or bilateral oophorectomy), or postmenopausal (defined as amenorrhea for 12 consecutive months and documented serum follicle-stimulating hormone level >40 IU/mL [confirmed at Screening]) are exempt from the contraception requirement.
- 3. The subject has a body mass index (BMI) at Screening of 18.0 to 32.0 kg/m2, inclusive, with a minimum weight of 47 kg for women and 66 kg for men.
- 4. The subject is not a smoker (or user of e-cigarettes).
- 5. The investigator considers the subject to be in good general health as determined by medical history, clinical laboratory test results, vital sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination findings at Screening and Check-in.
- 6. The subject agrees to comply with all protocol requirements as well as the particular requirements and specific Phase-I unit policies.
- 7. The subject provides written informed consent.
- 8. The subject has a creatinine level at or below the upper limit of normal.
- Exclusions: Subjects are excluded from the study if any of the following criteria are met:
- 1. The subject has a history of a relevant drug allergy or food allergy/sensitivity (e.g., allergy to rofecoxib or excipients of TRM-201 (including Captisol®-containing products), allergy to other non-steroidal anti-inflammatory drugs (NSAIDs), or gluten intolerance that could preclude consumption of a standard clinic diet).
- 2. A female subject is pregnant or lactating.
- 3. The subject has a history of intolerance or hypersensitivity to aspirin or any other NSAID.
- 4. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at Screening.
- 5. The subject has used any prescription (excluding hormonal birth control) or over the counter medications (OTC) including NSAIDs (e.g., ibuprofen, naproxen, and aspirin) as well as herbal or nutritional supplements, within 14 days (or 5 half-lives, whichever is longer) before the vehicle or study drug dosing. Subjects may have taken acetaminophen (up to 2 g per day) in the 14 days prior to but not the day before dosing in this study. Prescription and OTC medications as well as herbal or nutritional supplements are prohibited throughout the study. COVID-19 vaccines are accepted concomitant medications, but subjects are not to receive a COVID vaccination within 72 hours prior to check-in.
- 6. The subject has any clinically significant abnormalities before dosing on Day 1 or has a history of disease, including: uncontrolled or poorly controlled hypertension; asthma or pulmonary disease; major cardiac ischemic symptoms, events, or interventions such as angina pectoris, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, coronary stent or bypass; history of cerebrovascular ischemic events (transient ischemic attack or stroke); major vascular ischemic symptoms such as intermittent claudication or vascular bypass or replacement surgery; significant cardiovascular (CV), gastrointestinal (GI), neurological, endocrine, or renal disease; hepatic impairment; cholecystectomy; other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs; or clinically significant GI events.
- 7. The subject has a history or presence of any clinically significant abnormality in vital signs, ECG, or laboratory tests, or has any medical or psychiatric condition that, in the opinion of the investigator, may interfere with the study procedures or compromise subject safety (assessed at Screening and Check-in).
- 8. The subject is a cigarette smoker or has used nicotine or nicotine-containing products (e.g., snuff, nicotine patch, nicotine chewing gum, e-cigarettes) within 6 months prior to dosing in this study.
- 9. The subject has a history of alcohol abuse or drug addiction within the last year or consumes more than 1 unit (1 unit is equal to approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a day. Alcohol is not allowed within 7 days before study drug dosing.
- 10. The subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at Screening.
- 11. The subject is a habitual and heavy coffee drinker (more than 4 cups a day, 28 cups a week).
- 12. The subject is involved in strenuous activity or contact sports within 24 hours prior to dosing in this study.
- 13. The subject has donated blood or blood products within 30 days prior to dosing in this study.
- 14. The subject has received study drug in another investigational study within 30 days (or less than 5 half-lives of the investigational agent) prior to dosing in this study.
- 15. The subject is not suitable for entry into the study, in the opinion of the investigator.
- 16. The subject is an employee or family member of the investigator or clinic staff.
- 17. The subject has evidence of current SARS-CoV-2 infection.
- 18. The subject has poor venous access that limits phlebotomy.
- Continuing Eligibility at Check-In:
- 1. Females must have a negative serum pregnancy test.
- 2. All subjects must have a negative test result for drugs of abuse and alcohol.
- 3. Subjects must have had no significant changes in overall health status since screening including the use of medications.
- 4. The subject has not been involved in strenuous activity or contact sports within 24 hours prior to dosing in this study.
- 5. The subject has a creatinine level at or below the upper limit of normal.
- Safety:
- Safety and tolerability assessments will include monitoring and recording of adverse events (AEs), serious adverse events (SAEs), clinical laboratory assessments (hematology, serum chemistry, and urinalysis), vital sign measurements, 12-lead ECG assessments, and physical examination findings.
- Any abnormal laboratory test results (hematology, serum chemistry, or urinalysis) or other safety assessments (e.g., ECGs, vital sign measurements), including those that worsen from baseline, felt to be clinically significant in the medical and scientific judgment of the investigator are to be recorded as AEs or SAEs from the time a subject signs the informed consent. Adverse events of special interest (AESIs) will be noted as follows:
- Rofecoxib:
-
- Hypertension
- Congestive heart failure
- Lower extremity edema
- Upper GI perforations, ulcers, or bleeds
- Thrombotic CV events
- Pharmacokinetics:
- Plasma samples will be analyzed for TRM-201 using a validated method. The obtained plasma concentration-time data for TRM-201 will be analyzed using appropriate non compartmental techniques to obtain estimates of the following parameters, where appropriate and possible: Tlag, Tmax, Cmax, AUC0-24, AUC0-last, AUC0-inf, AUCextrap, t½, lambda-z, CL/F, Vz/F.
- Statistical Analysis:
- Statistical analysis will be performed using SAS software Version 9.4 or later.
- For categorical variables, frequencies and percentages will be presented. Continuous variables will be summarized using descriptive statistics (number of subjects, mean, standard deviation (SD), median, minimum, maximum). For PK-related data, geometric mean, geometric coefficient of variation (CV[%]) and geometric SD will also be provided.
- Baseline demographic and background variables will be summarized overall for all subjects. The number of subjects who enroll in the study and the number and percentage of subjects who complete the study will be presented. The frequency and percentage of subjects who withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, will also be summarized. Data will be listed in data listings.
- Analysis of Pharmacokinetic Endpoints:
- PK endpoints (both parameters and concentrations) will be summarized using descriptive statistics (number of subjects, mean, SD, median, minimum, maximum, geometric mean, geometric CV(%) and geometric SD). Data will be provided as data listings. Relative bioavailability will be estimated from the geometric mean ratio of Cmax, AUClast, and AUC0-inf (oral tablet versus oral solution) derived from a 2-period crossover model analysis of natural log transformed values. The associated 90% confidence interval will also be provided.
- Analysis of Safety:
- All safety data will be summarized, and the incidence of adverse events will be presented by the MedDRA system (Version 23.1 or a more recent version) organ class and preferred term, relationship to the test article, and severity.
- Serious AEs and AEs leading to discontinuation of study drug will also be presented in the data listings.
- Actual values and changes from Baseline for clinical laboratory test results, vital sign measurements, and 12-lead ECG results will be summarized at each time point using descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). Shift tables will be generated for clinical laboratory test results. Physical examination findings will be presented in a data listing.
- Pharmacokinetic Results:
-
FIG. 4 shows Cmax values for the tablet and oral solution (OS) formulations of rofecoxib (TRM-201).FIG. 4 shows that the Cmax values for almost every subject is higher for the oral solution formulation than for the tablet formulation of rofecoxib. This leads to a higher geometric mean value of 345.3 ng/ml for Cmax following oral solution administration compared to 289.1 ng/ml for Cmax following administration of the tablet formulation. -
FIG. 5 shows AUC for the tablet and oral solution (OS) formulations of rofecoxib (TRM-201).FIG. 5 shows that the AUC is equivalent for the tablet formulation of rofecoxib with a geometric mean AUC at 3817.3 ng*h/ml and the oral solution formulation of rofecoxib with a geometric mean AUC at 3840.2 ng*h/ml.
Claims (92)
1. A pharmaceutical composition comprising an aqueous solution comprising:
a) water,
b) a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and
c) a solubilizing agent,
wherein the solubility of the water insoluble COX-2 inhibitor in the solution is more than 10 μg/ml.
2. The pharmaceutical composition of claim 1 , wherein the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib.
3. The pharmaceutical composition of claim 1 , wherein the water insoluble COX-2 inhibitor is rofecoxib.
4. The pharmaceutical composition of claim 1 , wherein the composition further comprises at least one co-solvent helper.
5. The pharmaceutical composition of claim 1 , wherein the composition further comprises at least one antioxidant.
6. The pharmaceutical composition of claim 1 , wherein the composition further comprises at least one buffering agent.
7. The pharmaceutical composition of claim 1 , wherein the composition further comprises at least one isotonic agent.
8. The pharmaceutical composition of claim 1 , wherein said composition is a reconstituted lyophile.
9. The pharmaceutical composition of claim 8 , wherein said pharmaceutical composition is diluted prior to administration.
10. The pharmaceutical composition of claim 1 , wherein the solubilizing agent is a cyclodextrin.
11. The pharmaceutical composition of claim 10 , wherein the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof.
12. The pharmaceutical composition of claim 11 , wherein the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
13. The pharmaceutical composition of claim 12 , wherein the hydroxypropyl-β-cyclodextrin is Cavasol®.
14. The pharmaceutical composition of claim 11 , wherein the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
15. The pharmaceutical composition of claim 14 , wherein the sulfobutyl ether-β-cyclodextrin is Captisol®.
16. The pharmaceutical composition of claim 1 or 3 , having a therapeutically effective amount of the water insoluble COX-2 inhibitor in a single dose formulation, wherein the amount is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
17. The pharmaceutical composition of claim 1 or 3 , wherein the concentration % (w/v) of the water insoluble COX-2 inhibitor in the aqueous solution is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration.
18. The pharmaceutical composition of claim 1 or 3 , wherein the volume of the solution is selected from the group consisting of about 5 ml, about 10 ml, about 20 ml, about 25 mL, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume.
19. The pharmaceutical composition of claim 1 or 3 , wherein the solubility of the water insoluble COX-2 inhibitor in the solution is more than 20 μg/ml, more than 30 μg/ml, more than 40 μg/ml, more than 50 μg/ml, more than 60 μg/ml, more than 70 μg/ml, more than 80 μg/ml, more than 90 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ml, more than 130 μg/ml, more than 140 μg/ml, or more than 150 μg/ml.
20. The pharmaceutical composition of claim 1 , wherein said composition is administered as part of a combination therapy with at least one other therapeutic agent.
21. The pharmaceutical composition of claim 1 , wherein said composition is suitable for intravenous administration to a subject.
22. A lyophilized pharmaceutical composition comprising a lyophilization product of any of the pharmaceutical compositions of claim 1 or 3 .
23. A method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising parenterally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an aqueous solution comprising:
a) water,
b) a COX-2 inhibitor or a pharmaceutically acceptable salt or ester thereof, and
c) a solubilizing agent.
24. The method of claim 23 , wherein the water insoluble COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib.
25. The method of claim 24 , wherein the water insoluble COX-2 inhibitor is rofecoxib.
26. The method of claim 23 , wherein the composition further comprises at least one co-solvent helper.
27. The method of claim 23 , wherein the composition further comprises at least one antioxidant.
28. The method of claim 23 , wherein the composition further comprises at least one buffering agent.
29. The method of claim 23 , wherein the composition further comprises at least one isotonic agent.
30. The method of claim 23 , wherein said composition is a reconstituted lyophile.
31. The method of claim 30 , wherein said pharmaceutical composition is diluted.
32. The method of claim 23 , wherein the solubilizing agent is a cyclodextrin.
33. The method of claim 32 , wherein the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof.
34. The method of claim 33 , wherein the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
35. The method of claim 34 , wherein the hydroxypropyl-β-cyclodextrin is Cavasol®.
36. The method of claim 33 , wherein the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
37. The method of claim 36 , wherein the sulfobutyl ether-β-cyclodextrin is Captisol®.
38. The method of claim 23 or 25 , wherein the effective amount of the COX-2 inhibitor in a single dose formulation is selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
39. The method of claim 23 or 25 , wherein the concentration % (w/v) of the COX-2 inhibitor in an aqueous formulation is selected from the group consisting of about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.01%, about 0.012%, about 0.015%, about 0.017%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.05%, about 0.06%, about 0.07% and any other suitable concentration.
40. The method of claim 23 or 25 , wherein the volume of an aqueous formulations of the COX-2 inhibitor is selected from the group consisting of about 1 ml, about 2 ml, about 3 ml, about 4 ml, about 5 ml, about 10 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 180 ml, and any suitable volume.
41. The method of claim 23 or 25 , wherein the solubility of the COX-2 inhibitor is enhanced to more than 10 μg/ml, more than 20 μg/ml, more than 30 μg/ml, more than 40 μg/ml, more than 50 μg/ml, more than 60 μg/ml, more than 70 μg/ml, more than 80 μg/ml, more than 90 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ml, more than 130 μg/ml, more than 140 μg/ml, or more than 150 μg/ml.
42. The method of claim 23 , wherein said composition is administered as part of a combination therapy with at least one other therapeutic agent.
43. A lyophilized pharmaceutical composition comprising a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof and a solubilizing agent, wherein the lyophilized pharmaceutical composition is a produced by lyophilizing a pharmaceutical composition comprising an aqueous formulation comprising water, a water insoluble COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and a solubilizing agent.
44. A pharmaceutical composition comprising an oral solution comprising:
a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof, and
b) a solubilizing agent.
45. The pharmaceutical composition of claim 44 , wherein the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
46. The pharmaceutical composition of claim 44 , wherein the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib.
47. The pharmaceutical composition of claim 44 , wherein the COX-2 inhibitor is rofecoxib.
48. The pharmaceutical composition of claim 44 , wherein the composition further comprises at least one co-solvent helper.
49. The pharmaceutical composition of claim 44 , wherein the composition further comprises at least one antioxidant.
50. The pharmaceutical composition of claim 44 , wherein the composition further comprises at least one buffering agent.
51. The pharmaceutical composition of claim 44 , wherein the pharmaceutical composition is diluted prior to administration.
52. The pharmaceutical composition of claim 44 , wherein the solubilizing agent is a cyclodextrin.
53. The pharmaceutical composition of claim 52 , wherein the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof.
54. The pharmaceutical composition of claim 53 , wherein the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
55. The pharmaceutical composition of claim 54 , wherein the hydroxypropyl-β-cyclodextrin is Cavasol®.
56. The pharmaceutical composition of claim 53 , wherein the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
57. The pharmaceutical composition of claim 56 , wherein the sulfobutyl ether-β-cyclodextrin is Captisol®.
58. The pharmaceutical composition of claim 44 or 47 , wherein the pharmaceutical composition comprises an effective amount of the COX-2 inhibitor in a single dose selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
59. The pharmaceutical composition of claim 44 or 47 , wherein the oral solution has a volume selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume.
60. The pharmaceutical composition of claim 44 or 47 , wherein the oral solution comprises of about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
61. The pharmaceutical composition of claim 44 , wherein the pharmaceutical composition is administered as part of a combination therapy with at least one other therapeutic agent.
62. The pharmaceutical composition of claim 44 , wherein the pharmaceutical composition is suitable for oral administration to a subject.
63. The pharmaceutical composition of claim 44 or 47 , wherein the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
64. The pharmaceutical composition of claim 63 , wherein the geometric mean plasma AUC0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml.
65. The pharmaceutical composition of claim 44 , wherein the oral solution comprises rofecoxib and achieves a plasma AUC0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
66. The pharmaceutical composition of claim 44 , wherein the oral solution comprises rofecoxib and achieves a geometric mean plasma Cmax from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
67. The pharmaceutical composition of claim 66 , wherein the geometric mean plasma Cmax is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml.
68. The pharmaceutical composition of claim 44 or 47 , wherein the oral solution comprises rofecoxib and achieves a geometric mean plasma Cmax of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
69. A method for treatment of pain, fever, or inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an oral solution comprising:
a) a COX-2 inhibitor or a pharmaceutically acceptable salt, ester or co-crystal thereof; and
b) a solubilizing agent.
70. The pharmaceutical composition of claim 69 , wherein the COX-2 inhibitor is a water insoluble COX-2 inhibitor.
71. The method of claim 69 , wherein the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, and celecoxib.
72. The method of claim 69 , wherein the COX-2 inhibitor is rofecoxib.
73. The method of claim 69 , wherein the composition further comprises at least one co-solvent helper.
74. The method of claim 69 , wherein the composition further comprises at least one antioxidant.
75. The method of claim 69 , wherein the composition further comprises at least one buffering agent.
76. The method of claim 66 , wherein the pharmaceutical composition is diluted prior to administration.
77. The method of claim 66 , wherein the solubilizing agent is a cyclodextrin.
78. The method of claim 77 , wherein the cyclodextrin is selected from the group consisting of α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, and any mixtures thereof.
79. The method of claim 78 , wherein the β-cyclodextrin is a hydroxypropyl-β-cyclodextrin corresponding to the CAS Registry Number 128446-35-5.
80. The method of claim 79 , wherein the hydroxypropyl-β-cyclodextrin is Cavasol®.
81. The method of claim 78 , wherein the β-cyclodextrin is a sulfobutyl ether-β-cyclodextrin corresponding to the CAS Registry Number 182410-00-0.
82. The method of claim 81 , wherein the sulfobutyl ether-β-cyclodextrin is Captisol®.
83. The method of claim 69 or 72 , comprising an effective amount of the COX-2 inhibitor in a single dose selected from the group consisting of 2 mg, 3 mg, 5 mg, 6.25 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, and 70 mg.
84. The method of claim 69 or 72 , wherein the oral solution has a volume selected from the group consisting of about 5 ml, about 10 ml, about 15 ml, about 20 ml, about 25 ml, about 30 ml, about 40 ml, about 50 ml, about 60 ml, about 70 ml, about 80 ml, about 90 ml, about 100 ml, about 110 ml, about 120 ml, about 130 ml, about 140 ml, about 150 ml, about 160 ml, about 165 ml, about 170 ml, about 175 ml, about 180 ml, about 185 ml, about 190 ml, about 200 ml, or any suitable volume.
85. The method of claim 69 or 72 , wherein the oral solution comprises about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.08 mg/ml, about 0.09 mg/ml, about 0.1 mg/ml, about 0.11 mg/ml, about 0.12 mg/ml, about 0.13 mg/ml, about 0.14 mg/ml, or about 0.15 mg/ml of rofecoxib.
86. The method of claim 69 , wherein the composition is administered as part of a combination therapy with at least one other therapeutic agent.
87. The method of claim 69 , wherein the oral solution comprises rofecoxib and achieves a geometric mean plasma AUC0-48 hr from about 3053 to about 4772 h*ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
88. The method of claim 87 , wherein the geometric mean plasma AUC0-48 hr is about 3053 h*ng/ml, about 3100 h*ng/ml, about 3200 h*ng/ml, about 3300 h*ng/ml, about 3400 h*ng/ml, about 3500 h*ng/ml, about 3600 h*ng/ml, about 3700 h*ng/ml, about 3800 h*ng/ml, about 3900 h*ng/ml, about 4000 h*ng/ml, about 4100 h*ng/ml, about 4200 h*ng/ml, about 4300 h*ng/ml, about 4320 h*ng/ml, about 4500 h*ng/ml, about 4600 h*ng/ml, about 4700 h*ng/ml, or about 4772 h*ng/ml.
89. The method of claim 69 , wherein the oral solution comprises rofecoxib and achieves a plasma AUC0-48 hr of between 174.5 h*ng/ml and 276 h*ng/ml for each 1 mg of rofecoxib in the solution.
90. The method of claim 69 , wherein the oral solution comprises rofecoxib and achieves a geometric mean plasma Cmax from about 276 to about 432 ng/ml following administration of a single dose of the oral solution to a population of healthy adults less than 65 years of age.
91. The method of claim 90 , wherein the geometric mean plasma Cmax is about 276 ng/ml, about 290 ng/ml, about 300 ng/ml, about 310 ng/ml, about 320 ng/ml, about 330 ng/ml, about 340 ng/ml, about 350 ng/ml, about 360 ng/ml, about 370 ng/ml, about 380 ng/ml, about 390 ng/ml, about 400 ng/ml, about 410 ng/ml, about 420 ng/ml, about 430 ng/ml, or about 432 ng/ml.
92. The method of claim 69 , wherein the oral solution comprises rofecoxib and achieves a Cmax of between 16 ng/ml and 25.1 ng/ml for each 1 mg of rofecoxib in the solution.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/512,268 US20220125773A1 (en) | 2020-10-28 | 2021-10-27 | Aqueous formulations of water insoluble cox-2 inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063106571P | 2020-10-28 | 2020-10-28 | |
US17/512,268 US20220125773A1 (en) | 2020-10-28 | 2021-10-27 | Aqueous formulations of water insoluble cox-2 inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
US20220125773A1 true US20220125773A1 (en) | 2022-04-28 |
Family
ID=81258832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/512,268 Pending US20220125773A1 (en) | 2020-10-28 | 2021-10-27 | Aqueous formulations of water insoluble cox-2 inhibitors |
Country Status (6)
Country | Link |
---|---|
US (1) | US20220125773A1 (en) |
JP (1) | JP2023548380A (en) |
KR (1) | KR20230118081A (en) |
CN (1) | CN116782897A (en) |
CA (1) | CA3200132A1 (en) |
WO (1) | WO2022093978A1 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021124044A1 (en) * | 2019-12-16 | 2021-06-24 | Themis Medicare Limited | Pharmaceutical composition of cyclooxygenase – 2 inhibitors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20020146A1 (en) * | 2000-07-13 | 2002-03-31 | Upjohn Co | OPHTHALMIC FORMULATION INCLUDING A CYCLOOXYGENASE-2 (COX-2) INHIBITOR |
CA2476438A1 (en) * | 2002-02-22 | 2003-08-28 | Warner-Lambert Company Llc | Combinations of an alpha-2-delta ligand with a selective inhibitor of cyclooxygenase-2 |
EP2276463A4 (en) * | 2008-04-11 | 2013-12-04 | Univ Louisiana State | Diterpene glycosides as natural solubilizers |
KR101455901B1 (en) * | 2012-05-04 | 2014-11-03 | 성균관대학교산학협력단 | Eutectic composition comprising celecoxib and poloxamer |
US11154535B2 (en) * | 2012-07-31 | 2021-10-26 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
-
2021
- 2021-10-27 WO PCT/US2021/056878 patent/WO2022093978A1/en active Application Filing
- 2021-10-27 CA CA3200132A patent/CA3200132A1/en active Pending
- 2021-10-27 JP JP2023527232A patent/JP2023548380A/en active Pending
- 2021-10-27 US US17/512,268 patent/US20220125773A1/en active Pending
- 2021-10-27 CN CN202180084584.3A patent/CN116782897A/en active Pending
- 2021-10-27 KR KR1020237017903A patent/KR20230118081A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021124044A1 (en) * | 2019-12-16 | 2021-06-24 | Themis Medicare Limited | Pharmaceutical composition of cyclooxygenase – 2 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
JP2023548380A (en) | 2023-11-16 |
KR20230118081A (en) | 2023-08-10 |
CN116782897A (en) | 2023-09-19 |
CA3200132A1 (en) | 2022-05-05 |
WO2022093978A1 (en) | 2022-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10912744B2 (en) | Therapeutic formulation for reduced drug side effects | |
US20170065567A1 (en) | Pharmaceutical Suspension Composition | |
US8545879B2 (en) | Fast disintegrating compositions of meloxicam | |
BR112020012986A2 (en) | liquid oral formulations for pd v inhibitors | |
US20230263796A1 (en) | Pharmaceutical solution for oral dosage | |
US20240092797A1 (en) | Methods of making low odor choline salts of an organic compound | |
CZ2003966A3 (en) | Pharmaceutical preparation containing modafinil compound in a solution | |
US20170105983A1 (en) | Compositions for reduction of side effects | |
US20220125773A1 (en) | Aqueous formulations of water insoluble cox-2 inhibitors | |
US20040101563A1 (en) | Storage stable antihistaminic syrup formulations | |
GB2564444A (en) | Liquid pharmaceutical composition of flecainide | |
US20230086660A1 (en) | Oral formulations of metronidazole and methods of treating an infection using same | |
US20150306111A1 (en) | Pharmaceutical composition comprising desloratadine and prednisolone and their use | |
US20210322345A1 (en) | Midodrine hydrochloride oral solution and uses thereof | |
EP4370122A1 (en) | Method for treating sickle cell disease using quercetin-containing compositions | |
JP2016526553A (en) | Liquid pharmaceutical composition for oral administration containing fexofenadine | |
US20200330455A1 (en) | Method for treating neonatal opiod withdrawal syndrome | |
JP2022533510A (en) | Orally disintegrating tablets containing glycopyrrolate and methods for increasing bioavailability | |
JP3150642B2 (en) | Novel anticonvulsant and anti-inflammatory compositions and methods for their production | |
JPH10167988A (en) | Oral liquid preparation | |
US20230149306A1 (en) | Compositions and methods for treating sialorrhea | |
JPH05194232A (en) | Orally administering liquid agent of trimethoprim | |
JPH10203971A (en) | Aqueous oral solution | |
JP2007217434A (en) | Liquid agent for oral administration |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
AS | Assignment |
Owner name: TREMEAU PHARMACEUTICALS, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SIPPY, BRADFORD C.;SKWIERCZYNSKI, RAYMOND D.;SIGNING DATES FROM 20201110 TO 20201111;REEL/FRAME:062558/0349 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |